98 results on '"Luminal A breast cancer"'
Search Results
2. Two Different Immune Profiles Are Identified in Sentinel Lymph Nodes of Early-Stage Breast Cancer.
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Ribeiro, Joana Martins, Mendes, João, Gante, Inês, Figueiredo-Dias, Margarida, Almeida, Vânia, Gomes, Ana, Regateiro, Fernando Jesus, Regateiro, Frederico Soares, Caramelo, Francisco, and Silva, Henriqueta Coimbra
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BREAST cancer prognosis , *PROTEIN metabolism , *T cells , *KILLER cells , *RESEARCH funding , *BREAST tumors , *SENTINEL lymph nodes , *IMMUNE system , *GENE expression profiling , *TUMOR classification , *NUCLEIC acid amplification techniques , *B cells , *DENDRITIC cells - Abstract
Simple Summary: In this study, the researchers aimed to improve the prognostic information provided by the standard One-Step Nucleic Acid Amplification (OSNA) assay used to detect breast cancer (BC) metastasis in sentinel lymph nodes (SLNs). They analysed the expression of an immune gene panel in SLNs from Luminal A early-stage BC (cT1-T2 N0) patients, including those with and without subclinical metastasis. The study identified two distinct immune response profiles—one showing an adaptive anti-tumour immune response, and another with a more undifferentiated response. The researchers also identified seven key immunoregulatory genes that could serve as potential targets for immunotherapy. These findings suggest that analysing immune gene expression in SLNs can provide additional prognostic information beyond the OSNA assay results and may help guide personalised treatment approaches for early-stage BC patients. In the management of early-stage breast cancer (BC), lymph nodes (LNs) are typically characterised using the One-Step Nucleic Acid Amplification (OSNA) assay, a standard procedure for assessing subclinical metastasis in sentinel LNs (SLNs). The pivotal role of LNs in coordinating the immune response against BC is often overlooked. Our aim was to improve prognostic information provided by the OSNA assay and explore immune-related gene signatures in SLNs. The expression of an immune gene panel was analysed in SLNs from 32 patients with Luminal A early-stage BC (cT1-T2 N0). Using an unsupervised approach based on these expression values, this study identified two clusters, regardless of the SLN invasion: one evidencing an adaptive anti-tumoral immune response, characterised by an increase in naive B cells, follicular T helper cells, and activated NK cells; and another with a more undifferentiated response, with an increase in the activated-to-resting dendritic cells (DCs) ratio. Through a protein—protein interaction (PPI) network, we identified seven immunoregulatory hub genes: CD80, CD40, TNF, FCGR3A, CD163, FCGR3B, and CCR2. This study shows that, in Luminal A early-stage BC, SLNs gene expression studies enable the identification of distinct immune profiles that may influence prognosis stratification and highlight key genes that could serve as potential targets for immunotherapy. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
- View/download PDF
3. Impact of in vitro SARS-CoV-2 infection on breast cancer cells
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Michele Sommariva, Maria Dolci, Tiziana Triulzi, Federico Ambrogi, Matteo Dugo, Loris De Cecco, Valentino Le Noci, Giancarla Bernardo, Martina Anselmi, Elena Montanari, Serenella M. Pupa, Lucia Signorini, Nicoletta Gagliano, Lucia Sfondrini, Serena Delbue, and Elda Tagliabue
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SARS-CoV-2 ,Breast cancer ,Estrogen receptor ,Luminal A breast cancer ,Medicine ,Science - Abstract
Abstract The pandemic of coronavirus disease 19 (COVID-19), caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2), had severe repercussions for breast cancer patients. Increasing evidence indicates that SARS-CoV-2 infection may directly impact breast cancer biology, but the effects of SARS-CoV-2 on breast tumor cells are still unknown. Here, we analyzed the molecular events occurring in the MCF7, MDA-MB-231 and HCC1937 breast cancer cell lines, representative of the luminal A, basal B/claudin-low and basal A subtypes, respectively, upon SARS-CoV-2 infection. Viral replication was monitored over time, and gene expression profiling was conducted. We found that MCF7 cells were the most permissive to viral replication. Treatment of MCF7 cells with Tamoxifen reduced the SARS-CoV-2 replication rate, suggesting an involvement of the estrogen receptor in sustaining virus replication in malignant cells. Interestingly, a metagene signature based on genes upregulated by SARS-CoV-2 infection in all three cell lines distinguished a subgroup of premenopausal luminal A breast cancer patients with a poor prognosis. As SARS-CoV-2 still spreads among the population, it is essential to understand the impact of SARS-CoV-2 infection on breast cancer, particularly in premenopausal patients diagnosed with the luminal A subtype, and to assess the long-term impact of COVID-19 on breast cancer outcomes.
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- 2024
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- View/download PDF
4. Impact of in vitro SARS-CoV-2 infection on breast cancer cells.
- Author
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Sommariva, Michele, Dolci, Maria, Triulzi, Tiziana, Ambrogi, Federico, Dugo, Matteo, De Cecco, Loris, Le Noci, Valentino, Bernardo, Giancarla, Anselmi, Martina, Montanari, Elena, Pupa, Serenella M., Signorini, Lucia, Gagliano, Nicoletta, Sfondrini, Lucia, Delbue, Serena, and Tagliabue, Elda
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COVID-19 , *BREAST , *BREAST cancer , *SARS-CoV-2 , *CANCER cells , *COVID-19 pandemic - Abstract
The pandemic of coronavirus disease 19 (COVID-19), caused by severe respiratory syndrome coronavirus 2 (SARS-CoV-2), had severe repercussions for breast cancer patients. Increasing evidence indicates that SARS-CoV-2 infection may directly impact breast cancer biology, but the effects of SARS-CoV-2 on breast tumor cells are still unknown. Here, we analyzed the molecular events occurring in the MCF7, MDA-MB-231 and HCC1937 breast cancer cell lines, representative of the luminal A, basal B/claudin-low and basal A subtypes, respectively, upon SARS-CoV-2 infection. Viral replication was monitored over time, and gene expression profiling was conducted. We found that MCF7 cells were the most permissive to viral replication. Treatment of MCF7 cells with Tamoxifen reduced the SARS-CoV-2 replication rate, suggesting an involvement of the estrogen receptor in sustaining virus replication in malignant cells. Interestingly, a metagene signature based on genes upregulated by SARS-CoV-2 infection in all three cell lines distinguished a subgroup of premenopausal luminal A breast cancer patients with a poor prognosis. As SARS-CoV-2 still spreads among the population, it is essential to understand the impact of SARS-CoV-2 infection on breast cancer, particularly in premenopausal patients diagnosed with the luminal A subtype, and to assess the long-term impact of COVID-19 on breast cancer outcomes. [ABSTRACT FROM AUTHOR]
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- 2024
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- View/download PDF
5. Neoadjuvant Treatment of Locally-advanced Breast Cancer Patients With Ribociclib and Letrozole (NEOLETRIB)
- Author
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Novartis, Vestre Viken Hospital Trust, and Jurgen Geisler, Chief Physician
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- 2023
6. Two Different Immune Profiles Are Identified in Sentinel Lymph Nodes of Early-Stage Breast Cancer
- Author
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Joana Martins Ribeiro, João Mendes, Inês Gante, Margarida Figueiredo-Dias, Vânia Almeida, Ana Gomes, Fernando Jesus Regateiro, Frederico Soares Regateiro, Francisco Caramelo, and Henriqueta Coimbra Silva
- Subjects
Luminal A breast cancer ,sentinel lymph node ,immune microenvironment ,cancer genomics ,OSNA ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
In the management of early-stage breast cancer (BC), lymph nodes (LNs) are typically characterised using the One-Step Nucleic Acid Amplification (OSNA) assay, a standard procedure for assessing subclinical metastasis in sentinel LNs (SLNs). The pivotal role of LNs in coordinating the immune response against BC is often overlooked. Our aim was to improve prognostic information provided by the OSNA assay and explore immune-related gene signatures in SLNs. The expression of an immune gene panel was analysed in SLNs from 32 patients with Luminal A early-stage BC (cT1-T2 N0). Using an unsupervised approach based on these expression values, this study identified two clusters, regardless of the SLN invasion: one evidencing an adaptive anti-tumoral immune response, characterised by an increase in naive B cells, follicular T helper cells, and activated NK cells; and another with a more undifferentiated response, with an increase in the activated-to-resting dendritic cells (DCs) ratio. Through a protein—protein interaction (PPI) network, we identified seven immunoregulatory hub genes: CD80, CD40, TNF, FCGR3A, CD163, FCGR3B, and CCR2. This study shows that, in Luminal A early-stage BC, SLNs gene expression studies enable the identification of distinct immune profiles that may influence prognosis stratification and highlight key genes that could serve as potential targets for immunotherapy.
- Published
- 2024
- Full Text
- View/download PDF
7. CMA mediates resistance in breast cancer models
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Alessia Lo Dico, C. Martelli, F. Corsi, D. Porro, L. Ottobrini, and G. Bertoli
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HER2+ breast cancer ,Triple negative breast cancer ,Luminal A breast cancer ,Luminal B breast cancer ,Chaperone-mediated autophagy (CMA) ,Temozolomide (TMZ) ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Background Breast cancer (BC) is the most common malignancy in women and the second leading cause of cancer-related death; chemoresistance is still a clinical challenge mainly because of the different molecular features of this kind of tumour. Doxorubicin (Doxo) is widely used despite its adverse effects and the common onset of resistance. Chaperone-Mediated Autophagy (CMA) has been identified as an important mechanism through which chemotherapeutics can exert their cytotoxic effects and, in this context, LAMP-2A, the key player of CMA, can be a useful biomarker. Methods A cohort of patients and breast cancer cells have been screened for Doxo effect and CMA activation by analysing the LAMP-2A level. Molecular silencing has been used to clarify CMA role in BC responsiveness to treatments. Low Doxo doses were combined with other drugs (TMZ or PX-478, a HIF-1α inhibitor) to evaluate their cytotoxic ability and their role in modulating CMA. Results In this paper, we showed that CMA is an important mechanism mediating the responsiveness of breast cancer cell to different treatments (Doxo and TMZ, as suggested by triple negative cells that are TMZ-resistant and fails to activate CMA). The LAMP-2A expression level was specific for different cell lines and patient-derived tumour subtypes, and was also useful in discriminating patients for their survival rates. Moreover, molecular silencing or pharmacological blockage of HIF-1α activity reverted BC resistance to TMZ. The combination of low-dose Doxo with TMZ or PX-478 showed that the drug associations have synergistic behaviours. Conclusion Here, we demonstrated that CMA activity exerts a fundamental role in the responsiveness to different treatments, and LAMP-2A can be proposed as a reliable prognostic biomarker in breast cancer. In this context, HIF-1α, a potential target of CMA, can also be assessed as a valuable therapeutic target in BC in view of identifying new, more efficient and less toxic therapeutic drug combinations. Moreover, the possibility to combine Doxo with other drugs acting on different but coherent molecular targets could help overcome resistance and open the way to a decrease in the dose of the single drugs.
- Published
- 2023
- Full Text
- View/download PDF
8. A review on current and novel treatment regimen on luminal a breast cancer
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Bharti, Jayhind L, Wankhade, Anjali M, Vyas, J V, Paithankar, Vivek V, and Morey, Pratiksha R
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- 2023
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9. CMA mediates resistance in breast cancer models.
- Author
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Lo Dico, Alessia, Martelli, C., Corsi, F., Porro, D., Ottobrini, L., and Bertoli, G.
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BREAST cancer , *CANCER cell growth , *TRIPLE-negative breast cancer , *HER2 positive breast cancer - Abstract
Background: Breast cancer (BC) is the most common malignancy in women and the second leading cause of cancer-related death; chemoresistance is still a clinical challenge mainly because of the different molecular features of this kind of tumour. Doxorubicin (Doxo) is widely used despite its adverse effects and the common onset of resistance. Chaperone-Mediated Autophagy (CMA) has been identified as an important mechanism through which chemotherapeutics can exert their cytotoxic effects and, in this context, LAMP-2A, the key player of CMA, can be a useful biomarker. Methods: A cohort of patients and breast cancer cells have been screened for Doxo effect and CMA activation by analysing the LAMP-2A level. Molecular silencing has been used to clarify CMA role in BC responsiveness to treatments. Low Doxo doses were combined with other drugs (TMZ or PX-478, a HIF-1α inhibitor) to evaluate their cytotoxic ability and their role in modulating CMA. Results: In this paper, we showed that CMA is an important mechanism mediating the responsiveness of breast cancer cell to different treatments (Doxo and TMZ, as suggested by triple negative cells that are TMZ-resistant and fails to activate CMA). The LAMP-2A expression level was specific for different cell lines and patient-derived tumour subtypes, and was also useful in discriminating patients for their survival rates. Moreover, molecular silencing or pharmacological blockage of HIF-1α activity reverted BC resistance to TMZ. The combination of low-dose Doxo with TMZ or PX-478 showed that the drug associations have synergistic behaviours. Conclusion: Here, we demonstrated that CMA activity exerts a fundamental role in the responsiveness to different treatments, and LAMP-2A can be proposed as a reliable prognostic biomarker in breast cancer. In this context, HIF-1α, a potential target of CMA, can also be assessed as a valuable therapeutic target in BC in view of identifying new, more efficient and less toxic therapeutic drug combinations. Moreover, the possibility to combine Doxo with other drugs acting on different but coherent molecular targets could help overcome resistance and open the way to a decrease in the dose of the single drugs. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
10. Comprehensive proteome, phosphoproteome and kinome characterization of luminal A breast cancer.
- Author
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Ganglong Yang, Chenyang Zuo, Yuxiang Lin, Xiaoman Zhou, Piaopiao Wen, Chairui Zhang, Han Xiao, Meichen Jiang, Morihisa Fujita, Xiao-Dong Gao, and Fangmeng Fu
- Subjects
BREAST cancer ,LOBULAR carcinoma ,DUCTAL carcinoma ,PROTEIN expression ,AMP-activated protein kinases - Abstract
Background: Breast cancer is one of the most frequently occurring malignant cancers worldwide. Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the two most common histological subtypes of breast cancer. In this study, we aimed to deeply explore molecular characteristics and the relationship between IDC and ILC subtypes in luminal A subgroup of breast cancer using comprehensive proteomics and phosphoproteomics analysis. Methods: Cancer tissues and noncancerous adjacent tissues (NATs) with the luminal A subtype (ER- and PR-positive, HER2-negative) were obtained from paired IDC and ILC patients respectively. Label-free quantitative proteomics and phosphoproteomics methods were used to detect differential proteins and the phosphorylation status between 10 paired breast cancer and NATs. Then, the difference in protein expression and its phosphorylation between IDC and ILC subtypes were explored. Meanwhile, the activation of kinases and their substrates was also revealed by Kinase-Substrate Enrichment Analysis (KSEA). Results: In the luminal A breast cancer, a total of 5,044 high-confidence proteins and 3,808 phosphoproteins were identified from 10 paired tissues. The protein phosphorylation level in ILC tissues was higher than that in IDC tissues. Histone H1.10 was significantly increased in IDC but decreased in ILC, Conversely, complement C4-B and Crk-like protein were significantly decreased in IDC but increased in ILC. Moreover, the increased protein expression of Septin-2, Septin-9, Heterogeneous nuclear ribonucleoprotein A1 and Kinectin but reduce of their phosphorylation could clearly distinguish IDC from ILC. In addition, IDC was primarily related to energy metabolism and MAPK pathway, while ILC was more closely involved in the AMPK and p53/p21 pathways. Furthermore, the kinomes in IDC were primarily significantly activated in the CMGC groups. Conclusions: Our research provides insights into the molecular characterization of IDC and ILC and contributes to discovering novel targets for further drug development and targeted treatment. [ABSTRACT FROM AUTHOR]
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- 2023
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11. K-RAS Associated Gene-Mutation-Based Algorithm for Prediction of Treatment Response of Patients with Subtypes of Breast Cancer and Especially Triple-Negative Cancer.
- Author
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Johnson, Heather, Ali, Amjad, Zhang, Xuhui, Wang, Tianyan, Simoulis, Athanasios, Wingren, Anette Gjörloff, and Persson, Jenny L.
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DRUG efficacy , *STATISTICS , *GENETIC mutation , *CONFIDENCE intervals , *ONCOGENES , *CANCER chemotherapy , *MULTIVARIATE analysis , *MACHINE learning , *RANDOM forest algorithms , *CANCER patients , *DESCRIPTIVE statistics , *KAPLAN-Meier estimator , *PREDICTION models , *TUMOR markers , *DECISION making in clinical medicine , *PREDICTIVE validity , *LOGISTIC regression analysis , *PROGRESSION-free survival , *BREAST tumors , *ALGORITHMS , *LONGITUDINAL method , *PROPORTIONAL hazards models , *EVALUATION - Abstract
Simple Summary: Despite advances in treatment of subtypes of breast cancer, there still lacks reliable biomarkers with precision to predict treatment response at diagnosis. We used machine-learning tools and developed and validated a novel 12-Gene Algorithm as a biomarker for prediction of treatment response for breast cancer patients, especially those suffering triple-negative cancer. The 12-Gene Algorithm based on KRAS-associated gene-mutation profiles showed high accuracy at predicting the response of breast cancer patients including triple-negative subtype to first-line chemotherapy treatment in two independent patient cohorts. Our study suggests that the 12-Gene Algorithm has a potential to be used in clinical practice to improve breast cancer treatment decision-making, especially for triple-negative breast cancer patients. Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. Methods: Random Forest ML was applied to screen the algorithms of various combinations of gene mutation profiles of primary tumors at diagnosis using a TCGA Cohort (n = 399) with up to 150 months follow-up as a training set and validated in a MSK Cohort (n = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2−) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan–Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. Results: A novel algorithm termed the 12-Gene Algorithm based on mutation profiles of KRAS, PIK3CA, MAP3K1, MAP2K4, PTEN, TP53, CDH1, GATA3, KMT2C, ARID1A, RunX1, and ESR1, was identified. The performance of this algorithm to distinguish non-progressed (responder) vs. progressed (non-responder) to treatment in the TCGA Cohort as determined using AUC was 0.96 (95% CI 0.94–0.98). It predicted progression-free survival (PFS) with hazard ratio (HR) of 21.6 (95% CI 11.3–41.5) (p < 0.0001) in all patients. The algorithm predicted PFS in the triple-negative subgroup with HR of 19.3 (95% CI 3.7–101.3) (n = 42, p = 0.000). The 12-Gene Algorithm was validated in the MSK Cohort with a similar AUC of 0.97 (95% CI 0.96–0.98) to distinguish responder vs. non-responder patients, and had a HR of 18.6 (95% CI 4.4–79.2) to predict PFS in the triple-negative subgroup (n = 75, p < 0.0001). Conclusions: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has a potential to predict breast cancer treatment response to therapies, especially in triple-negative subgroups patients, which may assist personalized therapies and reduce mortality. [ABSTRACT FROM AUTHOR]
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- 2022
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12. Systematic functional interrogation of human pseudogenes using CRISPRi
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Ming Sun, Yunfei Wang, Caishang Zheng, Yanjun Wei, Jiakai Hou, Peng Zhang, Wei He, Xiangdong Lv, Yao Ding, Han Liang, Chung-Chau Hon, Xi Chen, Han Xu, and Yiwen Chen
- Subjects
Pseudogene ,Unitary pseudogene ,CRISPR interference ,Cancer ,Luminal A breast cancer ,Nucleus ,Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Background The human genome encodes over 14,000 pseudogenes that are evolutionary relics of protein-coding genes and commonly considered as nonfunctional. Emerging evidence suggests that some pseudogenes may exert important functions. However, to what extent human pseudogenes are functionally relevant remains unclear. There has been no large-scale characterization of pseudogene function because of technical challenges, including high sequence similarity between pseudogene and parent genes, and poor annotation of transcription start sites. Results To overcome these technical obstacles, we develop an integrated computational pipeline to design the first genome-wide library of CRISPR interference (CRISPRi) single-guide RNAs (sgRNAs) that target human pseudogene promoter-proximal regions. We perform the first pseudogene-focused CRISPRi screen in luminal A breast cancer cells and reveal approximately 70 pseudogenes that affect breast cancer cell fitness. Among the top hits, we identify a cancer-testis unitary pseudogene, MGAT4EP, that is predominantly localized in the nucleus and interacts with FOXA1, a key regulator in luminal A breast cancer. By enhancing the promoter binding of FOXA1, MGAT4EP upregulates the expression of oncogenic transcription factor FOXM1. Integrative analyses of multi-omic data from the Cancer Genome Atlas (TCGA) reveal many unitary pseudogenes whose expressions are significantly dysregulated and/or associated with overall/relapse-free survival of patients in diverse cancer types. Conclusions Our study represents the first large-scale study characterizing pseudogene function. Our findings suggest the importance of nuclear function of unitary pseudogenes and underscore their underappreciated roles in human diseases. The functional genomic resources developed here will greatly facilitate the study of human pseudogene function.
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- 2021
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13. Estrogen Receptor and Claudin-6 Might Play Vital Roles for Long-Term Prognosis in Patients With Luminal A Breast Cancer Who Underwent Neoadjuvant Chemotherapy.
- Author
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Liu, Yushi, Kang, Ye, Li, Jianyi, Zhang, Yang, Jia, Shi, Sun, Qiang, Ma, Yan, Zhang, Jing, Wang, Zhenrong, Cao, Yanan, and Shen, Yang
- Subjects
ESTROGEN receptors ,NEOADJUVANT chemotherapy ,BREAST cancer ,PROGNOSIS ,CANCER patients - Abstract
Purpose: It is well-known that the pathological complete response (pCR) rate in patients with luminal A cancer (LAC) is lower than those of other subtypes of breast cancer. The phenotype of cancer often alters after neoadjuvant chemotherapy (NAC) which may be related to hypoxia, and the latter might induce the drift of the estrogen receptor (ER). The phenotype drift in local advanced LAC after NAC might influence the long-term prognosis. Methods: The oxygen concentration of cancer tissues during NAC was recorded and analyzed (n = 43). The expression of ER and claudin-6 was detected in pre- and post-NAC specimens. Results: NAC might induce the cycling intracanceral hypoxia, and the pattern was related to NAC response. The median follow-up time was 61 months. Most of the patients (67%) with stable or increased ER and claudin-6 expression exhibited perfect prognosis (DFS = 100%, 61 months). About 20% of patients with decreased claudin-6 would undergo the poor prognosis (DFS = 22.2%, 61 months). The contrasting prognosis (100% vs. 22.2%) had nothing to do with the response of NAC in the above patients. Only 13% patients had stable claudin-6 and decreased ER, whose prognosis might relate to the response of NAC. Conclusion: NAC might induce cycling intracanceral hypoxia to promote the phenotype drift in local advanced LAC, and the changes in ER and claudin-6 after NAC would determine the long-term prognosis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
14. Estrogen Receptor and Claudin-6 Might Play Vital Roles for Long-Term Prognosis in Patients With Luminal A Breast Cancer Who Underwent Neoadjuvant Chemotherapy
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Yushi Liu, Ye Kang, Jianyi Li, Yang Zhang, Shi Jia, Qiang Sun, Yan Ma, Jing Zhang, Zhenrong Wang, Yanan Cao, and Yang Shen
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luminal A breast cancer ,cycling hypoxia ,estrogen receptor ,claudin-6 ,neoadjuvant chemotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
PurposeIt is well-known that the pathological complete response (pCR) rate in patients with luminal A cancer (LAC) is lower than those of other subtypes of breast cancer. The phenotype of cancer often alters after neoadjuvant chemotherapy (NAC) which may be related to hypoxia, and the latter might induce the drift of the estrogen receptor (ER). The phenotype drift in local advanced LAC after NAC might influence the long-term prognosis.MethodsThe oxygen concentration of cancer tissues during NAC was recorded and analyzed (n = 43). The expression of ER and claudin-6 was detected in pre- and post-NAC specimens.ResultsNAC might induce the cycling intracanceral hypoxia, and the pattern was related to NAC response. The median follow-up time was 61 months. Most of the patients (67%) with stable or increased ER and claudin-6 expression exhibited perfect prognosis (DFS = 100%, 61 months). About 20% of patients with decreased claudin-6 would undergo the poor prognosis (DFS = 22.2%, 61 months). The contrasting prognosis (100% vs. 22.2%) had nothing to do with the response of NAC in the above patients. Only 13% patients had stable claudin-6 and decreased ER, whose prognosis might relate to the response of NAC.ConclusionNAC might induce cycling intracanceral hypoxia to promote the phenotype drift in local advanced LAC, and the changes in ER and claudin-6 after NAC would determine the long-term prognosis.
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- 2022
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15. Characterization of Mitochondrial Proteome and Function in Luminal A and Basal-like Breast Cancer Subtypes Reveals Alteration in Mitochondrial Dynamics and Bioenergetics Relevant to Their Diagnosis.
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Ortega-Lozano, Ariadna Jazmín, Gómez-Caudillo, Leopoldo, Briones-Herrera, Alfredo, Aparicio-Trejo, Omar Emiliano, and Pedraza-Chaverri, José
- Subjects
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BIOENERGETICS , *BREAST cancer , *MITOCHONDRIA , *PROTEOMICS , *OXIDATIVE phosphorylation - Abstract
Breast cancer (BC) is the most prevalent cancer and the one with the highest mortality among women worldwide. Although the molecular classification of BC has been a helpful tool for diagnosing and predicting the treatment of BC, developments are still being made to improve the diagnosis and find new therapeutic targets. Mitochondrial dysfunction is a crucial feature of cancer, which can be associated with cancer aggressiveness. Although the importance of mitochondrial dynamics in cancer is well recognized, its involvement in the mitochondrial function and bioenergetics context in BC molecular subtypes has been scantly explored. In this study, we combined mitochondrial function and bioenergetics experiments in MCF7 and MDA-MB-231 cell lines with statistical and bioinformatics analyses of the mitochondrial proteome of luminal A and basal-like tumors. We demonstrate that basal-like tumors exhibit a vicious cycle between mitochondrial fusion and fission; impaired but not completely inactive mitochondrial function; and the Warburg effect, associated with decreased oxidative phosphorylation (OXPHOS) complexes I and III. Together with the results obtained in the cell lines and the mitochondrial proteome analysis, two mitochondrial signatures were proposed: one signature reflecting alterations in mitochondrial functions and a second signature exclusively of OXPHOS, which allow us to distinguish between luminal A and basal-like tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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16. Identification of key genes unique to the luminal a and basal-like breast cancer subtypes via bioinformatic analysis
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Rong Jia, Zhongxian Li, Wei Liang, Yucheng Ji, Yujie Weng, Ying Liang, and Pengfei Ning
- Subjects
Luminal a breast cancer ,Basal-like breast cancer ,Neoplasm genes ,Bioinformatics ,Surgery ,RD1-811 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Breast cancer subtypes are statistically associated with prognosis. The search for markers of breast tumor heterogeneity and the development of precision medicine for patients are the current focuses of the field. Methods We used a bioinformatic approach to identify key disease-causing genes unique to the luminal A and basal-like subtypes of breast cancer. First, we retrieved gene expression data for luminal A breast cancer, basal-like breast cancer, and normal breast tissue samples from The Cancer Genome Atlas database. The differentially expressed genes unique to the 2 breast cancer subtypes were identified and subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. We constructed protein–protein interaction networks of the differentially expressed genes. Finally, we analyzed the key modules of the networks, which we combined with survival data to identify the unique cancer genes associated with each breast cancer subtype. Results We identified 1114 differentially expressed genes in luminal A breast cancer and 1042 differentially expressed genes in basal-like breast cancer, of which the subtypes shared 500. We observed 614 and 542 differentially expressed genes unique to luminal A and basal-like breast cancer, respectively. Through enrichment analyses, protein–protein interaction network analysis, and module mining, we identified 8 key differentially expressed genes unique to each subtype. Analysis of the gene expression data in the context of the survival data revealed that high expression of NMUR1 and NCAM1 in luminal A breast cancer statistically correlated with poor prognosis, whereas the low expression levels of CDC7, KIF18A, STIL, and CKS2 in basal-like breast cancer statistically correlated with poor prognosis. Conclusions NMUR1 and NCAM1 are novel key disease-causing genes for luminal A breast cancer, and STIL is a novel key disease-causing gene for basal-like breast cancer. These genes are potential targets for clinical treatment.
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- 2020
- Full Text
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17. K-RAS Associated Gene-Mutation-Based Algorithm for Prediction of Treatment Response of Patients with Subtypes of Breast Cancer and Especially Triple-Negative Cancer
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Heather Johnson, Amjad Ali, Xuhui Zhang, Tianyan Wang, Athanasios Simoulis, Anette Gjörloff Wingren, and Jenny L. Persson
- Subjects
machine learning algorithm ,KRAS ,breast cancer biomarkers ,gene mutations ,triple-negative breast cancer ,luminal a breast cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. Methods: Random Forest ML was applied to screen the algorithms of various combinations of gene mutation profiles of primary tumors at diagnosis using a TCGA Cohort (n = 399) with up to 150 months follow-up as a training set and validated in a MSK Cohort (n = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2−) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan–Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. Results: A novel algorithm termed the 12-Gene Algorithm based on mutation profiles of KRAS, PIK3CA, MAP3K1, MAP2K4, PTEN, TP53, CDH1, GATA3, KMT2C, ARID1A, RunX1, and ESR1, was identified. The performance of this algorithm to distinguish non-progressed (responder) vs. progressed (non-responder) to treatment in the TCGA Cohort as determined using AUC was 0.96 (95% CI 0.94–0.98). It predicted progression-free survival (PFS) with hazard ratio (HR) of 21.6 (95% CI 11.3–41.5) (p < 0.0001) in all patients. The algorithm predicted PFS in the triple-negative subgroup with HR of 19.3 (95% CI 3.7–101.3) (n = 42, p = 0.000). The 12-Gene Algorithm was validated in the MSK Cohort with a similar AUC of 0.97 (95% CI 0.96–0.98) to distinguish responder vs. non-responder patients, and had a HR of 18.6 (95% CI 4.4–79.2) to predict PFS in the triple-negative subgroup (n = 75, p < 0.0001). Conclusions: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has a potential to predict breast cancer treatment response to therapies, especially in triple-negative subgroups patients, which may assist personalized therapies and reduce mortality.
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- 2022
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18. Acid-base transporters and pH dynamics in human breast carcinomas predict proliferative activity, metastasis, and survival
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Nicolai J Toft, Trine V Axelsen, Helene L Pedersen, Marco Mele, Mark Burton, Eva Balling, Tonje Johansen, Mads Thomassen, Peer M Christiansen, and Ebbe Boedtkjer
- Subjects
acid-base ,luminal A breast cancer ,metastasis ,microenvironment ,proliferation ,triple-negative breast cancer ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Breast cancer heterogeneity in histology and molecular subtype influences metabolic and proliferative activity and hence the acid load on cancer cells. We hypothesized that acid-base transporters and intracellular pH (pHi) dynamics contribute inter-individual variability in breast cancer aggressiveness and prognosis. We show that Na+,HCO3– cotransport and Na+/H+ exchange dominate cellular net acid extrusion in human breast carcinomas. Na+/H+ exchange elevates pHi preferentially in estrogen receptor-negative breast carcinomas, whereas Na+,HCO3– cotransport raises pHi more in invasive lobular than ductal breast carcinomas and in higher malignancy grade breast cancer. HER2-positive breast carcinomas have elevated protein expression of Na+/H+ exchanger NHE1/SLC9A1 and Na+,HCO3– cotransporter NBCn1/SLC4A7. Increased dependency on Na+,HCO3– cotransport associates with severe breast cancer: enlarged CO2/HCO3–-dependent rises in pHi predict accelerated cell proliferation, whereas enhanced CO2/HCO3–-dependent net acid extrusion, elevated NBCn1 protein expression, and reduced NHE1 protein expression predict lymph node metastasis. Accordingly, we observe reduced survival for patients suffering from luminal A or basal-like/triple-negative breast cancer with high SLC4A7 and/or low SLC9A1 mRNA expression. We conclude that the molecular mechanisms of acid-base regulation depend on clinicopathological characteristics of breast cancer patients. NBCn1 expression and dependency on Na+,HCO3– cotransport for pHi regulation, measured in biopsies of human primary breast carcinomas, independently predict proliferative activity, lymph node metastasis, and patient survival.
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- 2021
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19. Luminal A Breast Cancer Co-expression Network: Structural and Functional Alterations
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Diana García-Cortés, Enrique Hernández-Lemus, and Jesús Espinal-Enríquez
- Subjects
loss of long range co-expression ,gene co-expression networks ,Luminal A breast cancer ,breast cancer ,transcription factor analysis ,CTCF binding site analysis ,Genetics ,QH426-470 - Abstract
Luminal A is the most common breast cancer molecular subtype in women worldwide. These tumors have characteristic yet heterogeneous alterations at the genomic and transcriptomic level. Gene co-expression networks (GCNs) have contributed to better characterize the cancerous phenotype. We have previously shown an imbalance in the proportion of intra-chromosomal (cis-) over inter-chromosomal (trans-) interactions when comparing cancer and healthy tissue GCNs. In particular, for breast cancer molecular subtypes (Luminal A included), the majority of high co-expression interactions connect gene-pairs in the same chromosome, a phenomenon that we have called loss of trans- co-expression. Despite this phenomenon has been described, the functional implication of this specific network topology has not been studied yet. To understand the biological role that communities of co-expressed genes may have, we constructed GCNs for healthy and Luminal A phenotypes. Network modules were obtained based on their connectivity patterns and they were classified according to their chromosomal homophily (proportion of cis-/trans- interactions). A functional overrepresentation analysis was performed on communities in both networks to observe the significantly enriched processes for each community. We also investigated possible mechanisms for which the loss of trans- co-expression emerges in cancer GCN. To this end we evaluated transcription factor binding sites, CTCF binding sites, differential gene expression and copy number alterations (CNAs) in the cancer GCN. We found that trans- communities in Luminal A present more significantly enriched categories than cis- ones. Processes, such as angiogenesis, cell proliferation, or cell adhesion were found in trans- modules. The differential expression analysis showed that FOXM1, CENPA, and CIITA transcription factors, exert a major regulatory role on their communities by regulating expression of their target genes in other chromosomes. Finally, identification of CNAs, displayed a high enrichment of deletion peaks in cis- communities. With this approach, we demonstrate that network topology determine, to at certain extent, the function in Luminal A breast cancer network. Furthermore, several mechanisms seem to be acting together to avoid trans- co-expression. Since this phenomenon has been observed in other cancer tissues, a remaining question is whether the loss of long distance co-expression is a novel hallmark of cancer.
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- 2021
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20. Luminal A Breast Cancer Co-expression Network: Structural and Functional Alterations.
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García-Cortés, Diana, Hernández-Lemus, Enrique, and Espinal-Enríquez, Jesús
- Subjects
BREAST cancer ,GENE regulatory networks ,BINDING site assay ,BINDING sites ,GENE expression - Abstract
Luminal A is the most common breast cancer molecular subtype in women worldwide. These tumors have characteristic yet heterogeneous alterations at the genomic and transcriptomic level. Gene co-expression networks (GCNs) have contributed to better characterize the cancerous phenotype. We have previously shown an imbalance in the proportion of intra-chromosomal (cis-) over inter-chromosomal (trans-) interactions when comparing cancer and healthy tissue GCNs. In particular, for breast cancer molecular subtypes (Luminal A included), the majority of high co-expression interactions connect gene-pairs in the same chromosome, a phenomenon that we have called loss of trans- co-expression. Despite this phenomenon has been described, the functional implication of this specific network topology has not been studied yet. To understand the biological role that communities of co-expressed genes may have, we constructed GCNs for healthy and Luminal A phenotypes. Network modules were obtained based on their connectivity patterns and they were classified according to their chromosomal homophily (proportion of cis-/trans- interactions). A functional overrepresentation analysis was performed on communities in both networks to observe the significantly enriched processes for each community. We also investigated possible mechanisms for which the loss of trans- co-expression emerges in cancer GCN. To this end we evaluated transcription factor binding sites, CTCF binding sites, differential gene expression and copy number alterations (CNAs) in the cancer GCN. We found that trans- communities in Luminal A present more significantly enriched categories than cis- ones. Processes, such as angiogenesis, cell proliferation, or cell adhesion were found in trans- modules. The differential expression analysis showed that FOXM1, CENPA, and CIITA transcription factors, exert a major regulatory role on their communities by regulating expression of their target genes in other chromosomes. Finally, identification of CNAs, displayed a high enrichment of deletion peaks in cis- communities. With this approach, we demonstrate that network topology determine, to at certain extent, the function in Luminal A breast cancer network. Furthermore, several mechanisms seem to be acting together to avoid trans- co-expression. Since this phenomenon has been observed in other cancer tissues, a remaining question is whether the loss of long distance co-expression is a novel hallmark of cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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- View/download PDF
21. Characterization of Mitochondrial Proteome and Function in Luminal A and Basal-like Breast Cancer Subtypes Reveals Alteration in Mitochondrial Dynamics and Bioenergetics Relevant to Their Diagnosis
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Ariadna Jazmín Ortega-Lozano, Leopoldo Gómez-Caudillo, Alfredo Briones-Herrera, Omar Emiliano Aparicio-Trejo, and José Pedraza-Chaverri
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luminal A breast cancer ,basal-like breast cancer ,MCF7 cell line ,MDA-MB-231 cell line ,mitochondria dynamics ,mitochondrial biogenesis ,Microbiology ,QR1-502 - Abstract
Breast cancer (BC) is the most prevalent cancer and the one with the highest mortality among women worldwide. Although the molecular classification of BC has been a helpful tool for diagnosing and predicting the treatment of BC, developments are still being made to improve the diagnosis and find new therapeutic targets. Mitochondrial dysfunction is a crucial feature of cancer, which can be associated with cancer aggressiveness. Although the importance of mitochondrial dynamics in cancer is well recognized, its involvement in the mitochondrial function and bioenergetics context in BC molecular subtypes has been scantly explored. In this study, we combined mitochondrial function and bioenergetics experiments in MCF7 and MDA-MB-231 cell lines with statistical and bioinformatics analyses of the mitochondrial proteome of luminal A and basal-like tumors. We demonstrate that basal-like tumors exhibit a vicious cycle between mitochondrial fusion and fission; impaired but not completely inactive mitochondrial function; and the Warburg effect, associated with decreased oxidative phosphorylation (OXPHOS) complexes I and III. Together with the results obtained in the cell lines and the mitochondrial proteome analysis, two mitochondrial signatures were proposed: one signature reflecting alterations in mitochondrial functions and a second signature exclusively of OXPHOS, which allow us to distinguish between luminal A and basal-like tumors.
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- 2022
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22. ABTB2 Regulatory Variant as Predictor of Epirubicin-Based Neoadjuvant Chemotherapy in Luminal A Breast Cancer
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Yajie Gong, Nanlin Hu, Li Ma, Wentong Li, Xiang Cheng, Yi Zhang, Ying Zhu, Yang Yang, Xiating Peng, Danyi Zou, Jianbo Tian, Lan Yang, Shufang Mei, Xiaoyang Wang, Chun-han Lo, Jiang Chang, Tieying Hou, Hong Zhang, Binghe Xu, Rong Zhong, and Peng Yuan
- Subjects
luminal A breast cancer ,ABTB2 ,neoadjuvant chemotherapy ,epirubicin resistance ,single nucleotide polymorphism ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Epirubicin combined with docetaxel is the cornerstone of neoadjuvant chemotherapy (NAC) for breast cancer. The efficacy of NAC for luminal A breast cancer patients is very limited, and single nucleotide polymorphism is one of the most important factors that influences the efficacy. Our study is aimed to explore genetic markers for the efficacy of epirubicin combined with docetaxel for NAC in patients with luminal A breast cancer.Methods: A total of 421 patients with two stages of luminal A breast cancer were enrolled in this study from 2 centers. Among them 231 patients were included in the discovery cohort and 190 patients are in the replication cohort. All patients received epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1, in a 21-day cycle, a cycle for 2–6 cycles. Before treatment, 2 ml of peripheral blood was collected from each patient to isolate genomic DNA. Fourteen functional variants potentially regulating epirubicin/docetaxel response genes were prioritized by CellMiner and bioinformatics approaches. Moreover, biological assays were performed to determine the effect of genetic variations on response to chemotherapy.Results: The patients carrying rs6484711 variant A allele suffered a poor response to epirubicin and docetaxel for NAC (OR = 0.37, 95% CI: 0.18–0.74, P = 0.005) in combined stage. Moreover, expression quantitative trait loci (eQTL) analyses and luciferase reporter assays revealed that rs6484711 A allele significantly increased the expression of ABTB2. Subsequent biological assays illustrated that upregulation of ABTB2 significantly reduced the apoptosis rate of breast cancer cells and enhanced the chemo-resistance to epirubicin.Conclusions: Our study demonstrated rs6484711 polymorphism regulating ABTB2 expression might predict efficacy to epirubicin based NAC in luminal A breast cancer patients. These results provided valuable information about potential role of genetic variations in individualized chemotherapy.
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- 2020
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23. ABTB2 Regulatory Variant as Predictor of Epirubicin-Based Neoadjuvant Chemotherapy in Luminal A Breast Cancer.
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Gong, Yajie, Hu, Nanlin, Ma, Li, Li, Wentong, Cheng, Xiang, Zhang, Yi, Zhu, Ying, Yang, Yang, Peng, Xiating, Zou, Danyi, Tian, Jianbo, Yang, Lan, Mei, Shufang, Wang, Xiaoyang, Lo, Chun-han, Chang, Jiang, Hou, Tieying, Zhang, Hong, Xu, Binghe, and Zhong, Rong
- Subjects
CANCER chemotherapy ,BIOLOGICAL assay ,BIOLOGICAL variation ,SINGLE nucleotide polymorphisms ,BREAST cancer ,GENETIC markers - Abstract
Background: Epirubicin combined with docetaxel is the cornerstone of neoadjuvant chemotherapy (NAC) for breast cancer. The efficacy of NAC for luminal A breast cancer patients is very limited, and single nucleotide polymorphism is one of the most important factors that influences the efficacy. Our study is aimed to explore genetic markers for the efficacy of epirubicin combined with docetaxel for NAC in patients with luminal A breast cancer. Methods: A total of 421 patients with two stages of luminal A breast cancer were enrolled in this study from 2 centers. Among them 231 patients were included in the discovery cohort and 190 patients are in the replication cohort. All patients received epirubicin 75 mg/m
2 and docetaxel 75 mg/m2 on day 1, in a 21-day cycle, a cycle for 2–6 cycles. Before treatment, 2 ml of peripheral blood was collected from each patient to isolate genomic DNA. Fourteen functional variants potentially regulating epirubicin/docetaxel response genes were prioritized by CellMiner and bioinformatics approaches. Moreover, biological assays were performed to determine the effect of genetic variations on response to chemotherapy. Results: The patients carrying rs6484711 variant A allele suffered a poor response to epirubicin and docetaxel for NAC (OR = 0.37, 95% CI: 0.18–0.74, P = 0.005) in combined stage. Moreover, expression quantitative trait loci (eQTL) analyses and luciferase reporter assays revealed that rs6484711 A allele significantly increased the expression of ABTB2. Subsequent biological assays illustrated that upregulation of ABTB2 significantly reduced the apoptosis rate of breast cancer cells and enhanced the chemo-resistance to epirubicin. Conclusions: Our study demonstrated rs6484711 polymorphism regulating ABTB2 expression might predict efficacy to epirubicin based NAC in luminal A breast cancer patients. These results provided valuable information about potential role of genetic variations in individualized chemotherapy. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
24. Survival outcome of adjuvant endocrine therapy alone for patients with lymph node-positive, hormone-responsive, HER2-negative breast cancer.
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Jung, Sung Ui, Sohn, Guiyun, Kim, Jisun, Chung, Il Yong, Lee, Jong Won, Kim, Hee Jeong, Ko, Beom Seok, Son, Byung Ho, Ahn, Sei-Hyun, Yang, Seung Wook, and Lee, Sae Byul
- Abstract
The prognosis of hormone receptor-positive and HER2-negative breast cancer is better than that of other subtypes. Current guidelines recommend chemotherapy for N1 breast cancer patients. However, this has the possibility to be over-treatment. This was a retrospective study of 18,549 patients who were surgically treated for invasive breast cancer, at a single center in South Korea, between January 1993 and December 2012. N1 stage breast cancer patients who were hormone receptor-positive and HER2-negative were enrolled, and propensity score matching was performed to compare patients treated with anti-hormonal therapy alone (N = 83) and those treated with chemotherapy followed by anti-hormonal therapy (N = 85). In survival analysis, the survival parameters of the endocrine therapy-only group and the chemotherapy with endocrine therapy group were respectively 96.1% and 94.0% for 5-year recurrence free survival (RFS), 89.6% and 94.0% for 10-year RFS, 97.4% and 94.0% for 5-year distant metastasis-free survival (DMFS), 93.2% and 94.0% for 10-year DMFS, 98.7% and 98.8% for 10-year breast cancer-specific survival (BCSS), and 98.7% and 98.8% for 10-year overall survival (OS). There were no significant differences in RFS (p = 0.871), DMFS (p = 0.491), BCSS (p = 0.569) and OS (p = 0.731) between the two groups. Several patients with clinicopathologic features like hormone receptor positivity and HER2 negativity can avoid chemotherapy even with lymph node metastasis. Future studies with a long-term follow-up and a larger number of patients are required for validating our results. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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25. The cytotoxic potential of sinapic acid on luminal A breast cancer; a computational and experimental pharmacology approach.
- Author
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Dwivedi PSR and Shastry CS
- Abstract
Breast cancer is a highly concerning and prevalent disease that impacts a significant proportion of women worldwide, whose repeated exposure to therapies leads to resistance for drugs; making it alarming to identify novel chemotherapeutic agents. Sinapic acid is a phenolic acid that occurs naturally and is known to exhibit cytotoxic action in a variety of cancer cell types. In the present study, we utilized cell cytotoxicity assays to assess the cytotoxic potential of sinapic acid on various breast cancer subtypes. In addition, we assessed the cell migration rate, cell apoptosis, and cell cycle phases. Moreover, we utilized multiple system biology tools to predict the potential targets, and molecular docking was performed on the hub targets followed by molecular dynamic (MD) simulations. Cytotoxicity assay was performed on cell lines MCF7, T47D, MDA-MB-468, and SKBR3 at different time exposures of 24, 48, and 96 h. Our results revealed sinapic acid to be potent on MCF7 and T47D cell lines. The cell cycle analysis and cell apoptotic assays revealed sinapic acid to cause cell death by apoptosis majorly in the G0/G1 phase. Computational biology revealed KIF18B and VKORC1 to possess the highest binding affinity of -6.5 and -7.5 kcal/mol; displayed stable trajectories on MD run. The cytotoxicity of sinapic acid on luminal A cell lines may be due to the modulation of VKORC1 and KIF18B with major cell death in the G0/G1 phase. However, the mechanism has been proposed via in silico tools, which need further validation using wet lab protocols.Communicated by Ramaswamy H. Sarma.
- Published
- 2023
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26. Silencing human epidermal growth factor receptor‐3 radiosensitizes human luminal A breast cancer cells.
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He, Guofeng, Di, Xiaoke, Yan, Jingjing, Zhu, Caiqiang, Sun, Xinchen, and Zhang, Shu
- Abstract
Endocrine therapy and radiotherapy are the main treatments for luminal A breast cancer. However, drug and radiotherapy resistance could occur during long‐term treatment, leading to local recurrence and distant metastasis. Some studies have found that drug resistance might be related to human epidermal growth factor receptor‐3 (HER3) overexpression. However, whether HER3 plays a role in radiotherapy resistance is unknown. The purpose of this study is to elucidate the effect of HER3 in radiotherapy and to assess whether HER3 could be a potential target for radiosensitivity. We used retroviruses to construct stable low expression of HER3 in MCF‐7 and ZR75‐1cells. The CCK‐8 assay was used to observe proliferation. Colony‐forming assay was used to detect radiosensitivity. Flow cytometry was used to observe the cell cycle and apoptosis. Immunofluorescence assay was used to detect the number of γH2AX foci in the nucleus with or without ionizing radiation (IR). Western blot analysis was used to verify the change of relative proteins. Nude mice were used to observe tumor growth in vivo. In our study, silencing HER3 reduced cell proliferation and clone formation ability after IR, so silencing HER3 increased the sensitivity of luminal A breast cancer cells to radiotherapy. In terms of radiosensitivity mechanisms, it is suggested that the silencing of HER3 enhanced IR‐induced DNA damage, reduced DNA repair, and increased apoptosis and G2/M arrest. In addition, silencing HER3 combined with IR clearly inhibited the transplanted tumor growth in vivo. Therefore, we concluded that HER3 played a role in radiotherapy resistance. Silencing HER3 increased the radiosensitivity of luminal A breast cancer cells and HER3 could be a potential target for radiosensitivity. The purpose of this study is to elucidate the effect of human epidermal growth factor receptor‐3 (HER3) in radiotherapy resistance and further assess whether HER3 could be a potential target for radiosensitivity. We concluded that silencing HER3 could significantly increase the radiosensitivity of luminal A breast cancer cells and HER3 could be a potential target for radiotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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- View/download PDF
27. K-RAS associated gene-mutation-based algorithm for prediction of treatment response of patients with subtypes of breast cancer and especially triple-negative cancer
- Abstract
Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. Methods: Random Forest ML was applied to screen the algorithms of various combinations of gene mutation profiles of primary tumors at diagnosis using a TCGA Cohort (n = 399) with up to 150 months follow-up as a training set and validated in a MSK Cohort (n = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2−) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan–Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. Results: A novel algorithm termed the 12-Gene Algorithm based on mutation profiles of KRAS, PIK3CA, MAP3K1, MAP2K4, PTEN, TP53, CDH1, GATA3, KMT2C, ARID1A, RunX1, and ESR1, was identified. The performance of this algorithm to distinguish non-progressed (responder) vs. progressed (non-responder) to treatment in the TCGA Cohort as determined using AUC was 0.96 (95% CI 0.94–0.98). It predicted progression-free survival (PFS) with hazard ratio (HR) of 21.6 (95% CI 11.3–41.5) (p < 0.0001) in all patients. The algorithm predicted PFS in the triple-negative subgroup with HR of 19.3 (95% CI 3.7–101.3) (n = 42, p = 0.000). The 12-Gene Algorithm was validated in the MSK Cohort with a similar AUC of 0.97 (95% CI 0.96–0.98) to distinguish responder vs. non-responder patients, and had a HR of 18.6 (95% CI 4.4–79.2) to predict PFS in the triple-negative subgroup (n = 75, p < 0.0001). Conclusions: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has
- Published
- 2022
- Full Text
- View/download PDF
28. K-RAS Associated Gene-Mutation-Based Algorithm for Prediction of Treatment Response of Patients with Subtypes of Breast Cancer and Especially Triple-Negative Cancer
- Abstract
PURPOSE: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. METHODS: = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2-) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan-Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. RESULTS: < 0.0001). CONCLUSIONS: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has a potential to predict breast cancer treatment response to therapies, especially in triple-negative subgroups patients, which may assist personalized therapies and reduce mortality.
- Published
- 2022
- Full Text
- View/download PDF
29. K-RAS associated gene-mutation-based algorithm for prediction of treatment response of patients with subtypes of breast cancer and especially triple-negative cancer
- Abstract
Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. Methods: Random Forest ML was applied to screen the algorithms of various combinations of gene mutation profiles of primary tumors at diagnosis using a TCGA Cohort (n = 399) with up to 150 months follow-up as a training set and validated in a MSK Cohort (n = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2−) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan–Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. Results: A novel algorithm termed the 12-Gene Algorithm based on mutation profiles of KRAS, PIK3CA, MAP3K1, MAP2K4, PTEN, TP53, CDH1, GATA3, KMT2C, ARID1A, RunX1, and ESR1, was identified. The performance of this algorithm to distinguish non-progressed (responder) vs. progressed (non-responder) to treatment in the TCGA Cohort as determined using AUC was 0.96 (95% CI 0.94–0.98). It predicted progression-free survival (PFS) with hazard ratio (HR) of 21.6 (95% CI 11.3–41.5) (p < 0.0001) in all patients. The algorithm predicted PFS in the triple-negative subgroup with HR of 19.3 (95% CI 3.7–101.3) (n = 42, p = 0.000). The 12-Gene Algorithm was validated in the MSK Cohort with a similar AUC of 0.97 (95% CI 0.96–0.98) to distinguish responder vs. non-responder patients, and had a HR of 18.6 (95% CI 4.4–79.2) to predict PFS in the triple-negative subgroup (n = 75, p < 0.0001). Conclusions: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has
- Published
- 2022
- Full Text
- View/download PDF
30. K-RAS Associated Gene-Mutation-Based Algorithm for Prediction of Treatment Response of Patients with Subtypes of Breast Cancer and Especially Triple-Negative Cancer
- Abstract
PURPOSE: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. METHODS: = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2-) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan-Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. RESULTS: < 0.0001). CONCLUSIONS: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has a potential to predict breast cancer treatment response to therapies, especially in triple-negative subgroups patients, which may assist personalized therapies and reduce mortality.
- Published
- 2022
- Full Text
- View/download PDF
31. K-RAS associated gene-mutation-based algorithm for prediction of treatment response of patients with subtypes of breast cancer and especially triple-negative cancer
- Abstract
Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. Methods: Random Forest ML was applied to screen the algorithms of various combinations of gene mutation profiles of primary tumors at diagnosis using a TCGA Cohort (n = 399) with up to 150 months follow-up as a training set and validated in a MSK Cohort (n = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2−) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan–Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. Results: A novel algorithm termed the 12-Gene Algorithm based on mutation profiles of KRAS, PIK3CA, MAP3K1, MAP2K4, PTEN, TP53, CDH1, GATA3, KMT2C, ARID1A, RunX1, and ESR1, was identified. The performance of this algorithm to distinguish non-progressed (responder) vs. progressed (non-responder) to treatment in the TCGA Cohort as determined using AUC was 0.96 (95% CI 0.94–0.98). It predicted progression-free survival (PFS) with hazard ratio (HR) of 21.6 (95% CI 11.3–41.5) (p < 0.0001) in all patients. The algorithm predicted PFS in the triple-negative subgroup with HR of 19.3 (95% CI 3.7–101.3) (n = 42, p = 0.000). The 12-Gene Algorithm was validated in the MSK Cohort with a similar AUC of 0.97 (95% CI 0.96–0.98) to distinguish responder vs. non-responder patients, and had a HR of 18.6 (95% CI 4.4–79.2) to predict PFS in the triple-negative subgroup (n = 75, p < 0.0001). Conclusions: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has
- Published
- 2022
- Full Text
- View/download PDF
32. K-RAS associated gene-mutation-based algorithm for prediction of treatment response of patients with subtypes of breast cancer and especially triple-negative cancer
- Abstract
Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. Methods: Random Forest ML was applied to screen the algorithms of various combinations of gene mutation profiles of primary tumors at diagnosis using a TCGA Cohort (n = 399) with up to 150 months follow-up as a training set and validated in a MSK Cohort (n = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2−) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan–Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. Results: A novel algorithm termed the 12-Gene Algorithm based on mutation profiles of KRAS, PIK3CA, MAP3K1, MAP2K4, PTEN, TP53, CDH1, GATA3, KMT2C, ARID1A, RunX1, and ESR1, was identified. The performance of this algorithm to distinguish non-progressed (responder) vs. progressed (non-responder) to treatment in the TCGA Cohort as determined using AUC was 0.96 (95% CI 0.94–0.98). It predicted progression-free survival (PFS) with hazard ratio (HR) of 21.6 (95% CI 11.3–41.5) (p < 0.0001) in all patients. The algorithm predicted PFS in the triple-negative subgroup with HR of 19.3 (95% CI 3.7–101.3) (n = 42, p = 0.000). The 12-Gene Algorithm was validated in the MSK Cohort with a similar AUC of 0.97 (95% CI 0.96–0.98) to distinguish responder vs. non-responder patients, and had a HR of 18.6 (95% CI 4.4–79.2) to predict PFS in the triple-negative subgroup (n = 75, p < 0.0001). Conclusions: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has
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- 2022
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33. K-RAS associated gene-mutation-based algorithm for prediction of treatment response of patients with subtypes of breast cancer and especially triple-negative cancer
- Abstract
Purpose: There is an urgent need for developing new biomarker tools to accurately predict treatment response of breast cancer, especially the deadly triple-negative breast cancer. We aimed to develop gene-mutation-based machine learning (ML) algorithms as biomarker classifiers to predict treatment response of first-line chemotherapy with high precision. Methods: Random Forest ML was applied to screen the algorithms of various combinations of gene mutation profiles of primary tumors at diagnosis using a TCGA Cohort (n = 399) with up to 150 months follow-up as a training set and validated in a MSK Cohort (n = 807) with up to 220 months follow-up. Subtypes of breast cancer including triple-negative and luminal A (ER+, PR+ and HER2−) were also assessed. The predictive performance of the candidate algorithms as classifiers was further assessed using logistic regression, Kaplan–Meier progression-free survival (PFS) plot, and univariate/multivariate Cox proportional hazard regression analyses. Results: A novel algorithm termed the 12-Gene Algorithm based on mutation profiles of KRAS, PIK3CA, MAP3K1, MAP2K4, PTEN, TP53, CDH1, GATA3, KMT2C, ARID1A, RunX1, and ESR1, was identified. The performance of this algorithm to distinguish non-progressed (responder) vs. progressed (non-responder) to treatment in the TCGA Cohort as determined using AUC was 0.96 (95% CI 0.94–0.98). It predicted progression-free survival (PFS) with hazard ratio (HR) of 21.6 (95% CI 11.3–41.5) (p < 0.0001) in all patients. The algorithm predicted PFS in the triple-negative subgroup with HR of 19.3 (95% CI 3.7–101.3) (n = 42, p = 0.000). The 12-Gene Algorithm was validated in the MSK Cohort with a similar AUC of 0.97 (95% CI 0.96–0.98) to distinguish responder vs. non-responder patients, and had a HR of 18.6 (95% CI 4.4–79.2) to predict PFS in the triple-negative subgroup (n = 75, p < 0.0001). Conclusions: The novel 12-Gene algorithm based on multitude gene-mutation profiles identified through ML has
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- 2022
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34. Systematic functional interrogation of human pseudogenes using CRISPRi
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Chung Chau Hon, Wei He, Xi Chen, Han Xu, Ming Sun, Caishang Zheng, Xiangdong Lv, Jiakai Hou, Yanjun Wei, Yunfei Wang, Yiwen Chen, Han Liang, Peng Zhang, and Yao Ding
- Subjects
Hepatocyte Nuclear Factor 3-alpha ,Unitary pseudogene ,QH301-705.5 ,Pseudogene ,Breast Neoplasms ,Computational biology ,Biology ,QH426-470 ,Nucleus ,Transcriptional regulation ,Luminal A breast cancer ,medicine ,Genetics ,Humans ,Clustered Regularly Interspaced Short Palindromic Repeats ,Biology (General) ,Promoter Regions, Genetic ,Gene ,Transcription factor ,CRISPR interference ,Cell Proliferation ,Cancer ,Cell Nucleus ,Research ,Forkhead Box Protein M1 ,FOXM1 ,Computational Biology ,Reproducibility of Results ,TCGA ,medicine.disease ,Human genetics ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,MCF-7 Cells ,Human genome ,GTEx ,FOXA1 ,Pseudogenes ,Function (biology) ,Protein Binding ,RNA, Guide, Kinetoplastida - Abstract
BackgroundThe human genome encodes over 14,000 pseudogenes that are evolutionary relics of protein-coding genes and commonly considered as nonfunctional. Emerging evidence suggests that some pseudogenes may exert important functions. However, to what extent human pseudogenes are functionally relevant remains unclear. There has been no large-scale characterization of pseudogene function because of technical challenges, including high sequence similarity between pseudogene and parent genes, and poor annotation of transcription start sites.ResultsTo overcome these technical obstacles, we develop an integrated computational pipeline to design the first genome-wide library of CRISPR interference (CRISPRi) single-guide RNAs (sgRNAs) that target human pseudogene promoter-proximal regions. We perform the first pseudogene-focused CRISPRi screen in luminal A breast cancer cells and reveal approximately 70 pseudogenes that affect breast cancer cell fitness. Among the top hits, we identify a cancer-testis unitary pseudogene, MGAT4EP, that is predominantly localized in the nucleus and interacts with FOXA1, a key regulator in luminal A breast cancer. By enhancing the promoter binding of FOXA1, MGAT4EP upregulates the expression of oncogenic transcription factor FOXM1. Integrative analyses of multi-omic data from the Cancer Genome Atlas (TCGA) reveal many unitary pseudogenes whose expressions are significantly dysregulated and/or associated with overall/relapse-free survival of patients in diverse cancer types.ConclusionsOur study represents the first large-scale study characterizing pseudogene function. Our findings suggest the importance of nuclear function of unitary pseudogenes and underscore their underappreciated roles in human diseases. The functional genomic resources developed here will greatly facilitate the study of human pseudogene function.
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- 2021
35. Investigating a multigene prognostic assay based on significant pathways for Luminal A breast cancer through gene expression profile analysis.
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Gao, Haiyan, Yang, Mei, and Zhang, Xiaolan
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BREAST cancer prognosis , *TRANSCRIPTION factors , *GENE expression , *BIOINDICATORS , *CANCER relapse , *CANCER risk factors - Abstract
The present study aimed to investigate potential recurrence-risk biomarkers based on significant pathways for Luminal A breast cancer through gene expression profile analysis. Initially, the gene expression profiles of Luminal A breast cancer patients were downloaded from The Cancer Genome Atlas database. The differentially expressed genes (DEGs) were identified using a Limma package and the hierarchical clustering analysis was conducted for the DEGs. In addition, the functional pathways were screened using Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and rank ratio calculation. The multigene prognostic assay was exploited based on the statistically significant pathways and its prognostic function was tested using train set and verified using the gene expression data and survival data of Luminal A breast cancer patients downloaded from the Gene Expression Omnibus. A total of 300 DEGs were identified between good and poor outcome groups, including 176 upregulated genes and 124 downregulated genes. The DEGs may be used to effectively distinguish Luminal A samples with different prognoses verified by hierarchical clustering analysis. There were 9 pathways screened as significant pathways and a total of 18 DEGs involved in these 9 pathways were identified as prognostic biomarkers. According to the survival analysis and receiver operating characteristic curve, the obtained 18-gene prognostic assay exhibited good prognostic function with high sensitivity and specificity to both the train and test samples. In conclusion the 18-gene prognostic assay including the key genes, transcription factor 7-like 2, anterior parietal cortex and lymphocyte enhancer factor-1 may provide a new method for predicting outcomes and may be conducive to the promotion of precision medicine for Luminal A breast cancer. [ABSTRACT FROM AUTHOR]
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- 2018
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36. Systematic functional interrogation of human pseudogenes using CRISPRi
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Sun, Ming, Wang, Yunfei, Zheng, Caishang, Wei, Yanjun, Hou, Jiakai, Zhang, Peng, He, Wei, Lv, Xiangdong, Ding, Yao, Liang, Han, Hon, Chung-Chau, Chen, Xi, Xu, Han, and Chen, Yiwen
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- 2021
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37. Relative and Absolute Expression Analysis of MicroRNAs Associated with Luminal A Breast Cancer– A Comparison
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Arabkari, Vahid, Clancy, Eoin, Dwyer, Róisín M., Kerin, Michael J., Kalinina, Olga, Holian, Emma, Newell, John, and Smith, Terry J.
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- 2020
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38. Relationships of 18F-FDG uptake by primary tumors with prognostic factors and molecular subtype in ductal breast cancer
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Sengöz T., Karakaya Y.A., Gültekin A., Yaylali O., Senol H., and Yuksel D.
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p53 ,cancer patient ,luminal A breast cancer ,diagnostic imaging ,retrospective study ,Breast Neoplasms ,cancer prognosis ,Article ,Molecular subtype ,breast cancer ,primary tumor ,distant metastasis ,Fluorodeoxyglucose F18 ,lymphadenopathy ,Positron Emission Tomography Computed Tomography ,Humans ,invasive ductal breast carcinoma ,breast cancer molecular subtype ,human ,axillary lymphadenopathy ,Retrospective Studies ,breast tumor ,cancer staging ,correlational study ,SUVmax ,hormone receptor ,prediction ,basal subtype breast cancer ,Prognosis ,Ductal breast cancer ,major clinical study ,axillary lymph node ,18F-FDG ,fluorodeoxyglucose f 18 ,female ,tumor volume ,cancer grading ,histopathology ,positron emission tomography-computed tomography ,Ki 67 antigen ,maximum standardized uptake value - Abstract
Objectives: In this study, we aimed to investigate the correlation between SUVmax of primary tumor and prognostic factors/molecular subtype in ductal breast cancer patients. Materials and methods: We retrospectively reviewed 150 female patients with pathologically proven invasive ductal breast cancer from January 2015 to October 2019 who underwent 18F-FDG PET/CT for initial staging. Histopathological prognostic features of the primary tumor (histological grade, hormone receptor status, Ki-67 index, vb.) were obtained from the tru-cut biopsy report. In 18F-FDG PET/CT studies, the maximum standardized uptake value (SUVmax) of the primary breast tumor was calculated and compared with the presence of axillary lymphadenopathy and/or distant metastases, histopathological prognostic factors and molecular subtype. Results: The high SUVmax of primary breast tumors is significantly correlated with the clinicopathological factors: high tumor size, high histologic grade, high Ki-67 index, axillary lymph node positivity and distant metastasis. SUVmax value was significantly higher in patients with basal subtype than patients with Luminal A subtype (8.14 ± 3.71 and 4.64 ± 2.45, p = 0.002). Correlation analysis revealed a low correlation between Ki-67 index and SUVmax (r = 0.276, p = 0.001) and moderate correlation between tumor size and SUVmax (r = 0.470, p = 0.001). In multivariate linear regression analysis, Ki-67 index and tumor size had a statistically significant effect on SUVmax values. As these parameters increase, it is seen that it increases SUVmax values (p = 0.004, Std Beta: 0.228, 95% CI: 0.010–0.055 and p = 0.001, Std Beta: 0.374, 95% CI: 0.55–0.136, respectively). Conclusión: High SUVmax value is associated with prognotic factors suggesting poor prognosis. Pretreatment 18F-FDG PET/CT can be used as a tool to predict prognosis in breast cancer. © 2021 Sociedad Española de Medicina Nuclear e Imagen Molecular
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- 2022
39. Clinicopathologic features and genetic characteristics of the BRCA1/2 mutation in Turkish breast cancer patients
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Ismet Tasdelen, Ufuk Unal, Gamze Guney Eskiler, Erdem Cubukcu, Sibel Kahraman Çetintaş, Mustafa Sehsuvar Gokgoz, Havva Tezcan, Gulsah Cecener, Secil Ak Aksoy, Berrin Tunca, Maryam Sabour Takanlou, Unal Egeli, Turkkan Evrensel, Leila Sabour Takanlou, Isil Ezgi Eryilmaz, Bursa Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Biyoloji ve Genetik Anabilim Dalı., Bursa Uludağ Üniversitesi/Tıp Fakültesi/Genel Cerrahi Anabilim Dalı., Bursa Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Onkoloji Anabilim Dalı., Bursa Uludağ Üniversitesi/Tıp Fakültesi/Radyasyon Onkolojisi Anabilim Dalı., Çeçener, Gülşah, Takanlou, Leila Sabour, Takanlou, Maryam Sabour, Egeli, Ünal, Aksoy, Seçil, Ünal, Ufuk, Tezcan, Havva, Eryılmaz, Işıl Ezgi, Gökgöz, Mustafa Şehsuvar, Tunca, Berrin, Çubukçu, Erdem, Evrensel, Türkkan, Çetintaş, Sibel, Taşdelen, İsmet, GGI-6227-2022, EAS-6830-2022, GYU-0252-2022, EWY-5692-2022, ETP-1691-2022, EOI-5652-2022, and EBN-1186-2022
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Male ,Oncology ,Kaplan Meier method ,Turkey ,endocrine system diseases ,Epidemiology ,DNA Mutational Analysis ,Gene mutation ,Germline ,Heteroduplex analysis ,Human epidermal growth factor receptor 2 positive breast cancer ,Breast cancer ,0302 clinical medicine ,Pathology ,Tumor suppressor gene ,Disease free survival ,skin and connective tissue diseases ,030220 oncology & carcinogenesis ,Cohort analysis ,Breast carcinoma ,Human ,medicine.medical_specialty ,Ovarian-cancer ,Major clinical study ,Article ,Disease-Free Survival ,Cancer grading ,03 medical and health sciences ,Genetic screening ,Genetics ,Pathogenicity ,Humans ,Women ,Vairants ,Molecular Biology ,Genetic predisposition ,Follow up ,BRCA1 ,medicine.disease ,BRCA2 ,Gene frequency ,BRCA2 protein, human ,Mutation ,Sanger sequencing ,Cancer Research ,Kaplan-Meier Estimate ,Associations ,Turkey (republic) ,Turkey (bird) ,Germline mutation ,Pathogenic mutations ,Prevalence ,Tumor volume ,Overall survival ,Triple negative breast cancer ,Breast ,Family history ,Priority journal ,BRCA1 Protein ,Genetics & heredity ,Tumor characteristics ,Middle Aged ,Mutation (genetic algorithm) ,symbols ,Female ,Variant of uncertain significance ,Genetic trait ,Risk ,Adult ,Heterozygote ,BRCA1 Gene ,Breast Neoplasms ,Germline Mutation ,Ovary cancer ,Luminal B breast cancer ,Breast tumor ,Biology ,Breast Neoplasms, Male ,symbols.namesake ,Luminal A breast cancer ,Internal medicine ,medicine ,Genetic Predisposition to Disease ,Mortality ,Germline mutations ,Popoulation ,Germ-Line Mutation ,BRCA1 protein, human ,BRCA2 Protein ,Clinical feature ,Genetic association ,Physical-activity ,Genetic variability ,Ovarian cancer ,Controlled study ,Follow-Up Studies - Abstract
The aim of this study was to identify the frequency and spectrum of germline BRCA1/2 pathogenic alterations in a cohort of patients with breast carcinoma. In this study, a total of 603 breast cancer subjects from Turkey were screened for BRCA1/BRCA2 mutations using HDA and Sanger sequencing. In the present study, 21 BRCA1 and BRCA2 pathogenic variants were detected in 30 patients and BRCA1/2 mutations were significantly associated with a family history of breast/ovarian cancer. Analysis of overall survival for BRCA1/BRCA2 mutation carriers showed a trend for poor overall survival only in BRCA1 carriers, although this was not statistically significant in BRCA1 and BRCA2 mutation carriers. The c.5266dupC mutation is one of the most frequently reported mutations in BRCA1 and was identified in five breast cancer patients in our study. The most common BRCA2 gene mutations in the present study were c.8940delA and c.9097dupA, which were found in seven patients. We found mostly BRCA1 and BRCA2 mutation carriers in those patients who showed hormone-positive features. In conclusion, our data showed differences in the distribution of the mutation spectrum of BRCA1 and BRCA2 in Turkey.
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- 2020
40. Comprehensive proteome, phosphoproteome and kinome characterization of luminal A breast cancer.
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Yang G, Zuo C, Lin Y, Zhou X, Wen P, Zhang C, Xiao H, Jiang M, Fujita M, Gao XD, and Fu F
- Abstract
Background: Breast cancer is one of the most frequently occurring malignant cancers worldwide. Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the two most common histological subtypes of breast cancer. In this study, we aimed to deeply explore molecular characteristics and the relationship between IDC and ILC subtypes in luminal A subgroup of breast cancer using comprehensive proteomics and phosphoproteomics analysis., Methods: Cancer tissues and noncancerous adjacent tissues (NATs) with the luminal A subtype (ER- and PR-positive, HER2-negative) were obtained from paired IDC and ILC patients respectively. Label-free quantitative proteomics and phosphoproteomics methods were used to detect differential proteins and the phosphorylation status between 10 paired breast cancer and NATs. Then, the difference in protein expression and its phosphorylation between IDC and ILC subtypes were explored. Meanwhile, the activation of kinases and their substrates was also revealed by Kinase-Substrate Enrichment Analysis (KSEA)., Results: In the luminal A breast cancer, a total of 5,044 high-confidence proteins and 3,808 phosphoproteins were identified from 10 paired tissues. The protein phosphorylation level in ILC tissues was higher than that in IDC tissues. Histone H1.10 was significantly increased in IDC but decreased in ILC, Conversely, complement C4-B and Crk-like protein were significantly decreased in IDC but increased in ILC. Moreover, the increased protein expression of Septin-2, Septin-9, Heterogeneous nuclear ribonucleoprotein A1 and Kinectin but reduce of their phosphorylation could clearly distinguish IDC from ILC. In addition, IDC was primarily related to energy metabolism and MAPK pathway, while ILC was more closely involved in the AMPK and p53/p21 pathways. Furthermore, the kinomes in IDC were primarily significantly activated in the CMGC groups., Conclusions: Our research provides insights into the molecular characterization of IDC and ILC and contributes to discovering novel targets for further drug development and targeted treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yang, Zuo, Lin, Zhou, Wen, Zhang, Xiao, Jiang, Fujita, Gao and Fu.)
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- 2023
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41. A nanomedicine based combination therapy based on QLPVM peptide functionalized liposomal tamoxifen and doxorubicin against Luminal A breast cancer.
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Wang, Xiaoyou, Chen, Xianhui, Yang, Xiucong, Gao, Wei, He, Bing, Dai, Wenbing, Zhang, Hua, Wang, Xueqing, Wang, Jiancheng, Zhang, Xuan, Dai, Zhifei, and Zhang, Qiang
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BREAST cancer treatment ,NANOMEDICINE ,TAMOXIFEN ,DOXORUBICIN ,CANCER chemotherapy ,ESTROGEN receptors - Abstract
Though combination chemotherapy or antitumor nanomedicine is extensively investigated, their combining remains in infancy. Additionally, enhanced delivery of estrogen or its analogs to tumor with highly-expressed estrogen-receptor (ER) is seldom considered, despite its necessity for ER-positive breast cancer treatment. Here, nanomedicine based combination therapy using QLPVM conjugated liposomal tamoxifen (TAM) and doxorubicin (DOX) was designed and testified, where the penta-peptide was derived from Ku70 Bax-binding domain. Quantitative, semi-quantitative and qualitative approaches demonstrated the enhanced endocytosis and cytotoxicity of QLPVM conjugated sterically stabilized liposomes (QLPVM-SSLs) in vitro and in vivo . Mechanism studies of QLPVM excluded the possible electrostatic, hydrophobic or receptor–ligand interactions. However, as a weak cell-penetrating peptide, QLPVM significantly induced drug release from QLPVM-SSLs during their interaction with cells, which was favorable for drug internalization. These findings suggested that the nanomedicine based combination therapy using QLPVM-SSL-TAM and QLPVM-SSL-DOX might provide a rational strategy for Luminal A breast cancer. From the Clinical Editor Breast cancer remains a leading cause of mortality in women worldwide. Although combined therapy using hormonal antagonist and chemotherapy is the norm nowadays, the use of these agents together in a single delivery system has not been tested. Here, the authors investigated this approach using QLPVM conjugated liposomes in in-vitro and in-vivo models. The positive findings may provide a novel direction for breast cancer treatment in the near future. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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42. Identification of key genes unique to the luminal a and basal-like breast cancer subtypes via bioinformatic analysis
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Jia, Rong, Li, Zhongxian, Liang, Wei, Ji, Yucheng, Weng, Yujie, Liang, Ying, and Ning, Pengfei
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- 2020
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43. Evaluation of Kinetic Effects of Baicalein in Different Breast Cancer Cell Lines
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Mehmet Rıfkı Topçul
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baicalein ,lcsh:TA1-2040 ,luminal a breast cancer ,triple negative breast cancer ,üçlü negatif meme kanseri ,luminal a meme kanseri ,lcsh:Q ,skin and connective tissue diseases ,lcsh:Engineering (General). Civil engineering (General) ,lcsh:Science ,lcsh:Science (General) ,lcsh:Q1-390 - Abstract
The aim of this study was to compare the antiproliferative effects of baicalein which is a flavonoide on MCF-7 and MDA-MB-231 cell line. The experiments were carried out with the evaluation of the parameters. Including cell viability, cell index, mitotic index, labelling index and apoptotic index. With the cell viability test, IC50 concentrations of baicalein for MCF-7 and MDA-MB-231 cells were determined as 10 µM and 30 µM, respectively and these concentrations were used in all experiments. The results showed that the IC50 concentrations decreased the values of cell viability, cell index, mitotic index and labelling index and increased the apoptotic index value for both cell types. These decreases and increases are statistically significant (p
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- 2019
44. The heterogeneous subclones might be induced by cycling hypoxia which was aggravated along with the luminal A tumor growth.
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Kang, Yue and Li, Jianyi
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TUMOR growth ,HYPOXEMIA ,ULTRASONIC imaging ,TREATMENT failure ,THREE-dimensional imaging - Abstract
In process of infiltrating growth in solid tumor, the tumor cells undergo a periodic hypoxia/reoxygenation (circulating hypoxia) microenvironment, which might be one of principle reasons to promote formation of tumor heterogeneity and treatment failure. Therefore, it is very important to study how the microenvironment of circulating hypoxia induces the heterogeneous subclones in tumors. The maximum cross-section of luminal A tumor (LAT) was selected for the expression of hypoxia inducible factor-1 alpha (HIF-1 alpha) and estrogen receptor-alpha (ER-alpha), and the correlation between it and tumor diameter was observed. The distribution of intratumoral micro-vessels were analyzed by 3D reconstruction and CD34 staining. A circulating hypoxia model of MCF-7 was established to detect the HIF-1alpha and ER-alpha. There was a negative correlation between the expressions of ER-alpha and HIF-1alpha (c=−2.40; p = 0.044) in the LAT. As shown by 3D ultrasound image, there were less functional micro-vessels in the center than the periphery of tumor(P < 0.05). ER-alpha expression gradually decreased with the time course of cycling hypoxia, which is inversely related to the expression of HIF-1alpha. LAT is composed of heterogeneous subclone cells which can be distinguished by ER-alpha and HIF-1alpha, which was closely related with cycling hypoxia microenvironment. • The tumor cells undergo circulating hypoxia might promote formation of tumor heterogeneity and treatment failure. • It is very important to study how the microenvironment of circulating hypoxia induces the heterogeneous subclones in tumors. • Estrogen receptor-alpha and hypoxia inducible factor-1alpha were closely related with cycling hypoxia microenvironment. • Our study suggested that luminal A tumor was composed of heterogeneous subclone cells, which could be distinguished by HIF-1alpha and ER-alpha. • The heterogeneity between edge and center of the tumor aggravated along with the primary tumor growth. [ABSTRACT FROM AUTHOR]
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- 2022
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45. Silencing human epidermal growth factor receptor‐3 radiosensitizes human luminal A breast cancer cells
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Caiqiang Zhu, Shu Zhang, Xinchen Sun, Guofeng He, Xiaoke Di, and Jingjing Yan
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0301 basic medicine ,Cancer Research ,luminal A breast cancer ,Receptor, ErbB-3 ,Carcinogenesis ,Cell Survival ,DNA repair ,medicine.medical_treatment ,mechanism ,Mice, Nude ,Breast Neoplasms ,Biology ,Radiation Tolerance ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,HER3 ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Gene silencing ,Gene Silencing ,Radiosensitivity ,RNA, Small Interfering ,skin and connective tissue diseases ,Cell Proliferation ,Cell growth ,Original Articles ,General Medicine ,Cell cycle ,medicine.disease ,Combined Modality Therapy ,Xenograft Model Antitumor Assays ,body regions ,Radiation therapy ,030104 developmental biology ,Oncology ,radiosensitivity ,Apoptosis ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Cancer research ,Original Article ,Female ,ionizing radiation - Abstract
Endocrine therapy and radiotherapy are the main treatments for luminal A breast cancer. However, drug and radiotherapy resistance could occur during long-term treatment, leading to local recurrence and distant metastasis. Some studies have found that drug resistance might be related to human epidermal growth factor receptor-3 (HER3) overexpression. However, whether HER3 plays a role in radiotherapy resistance is unknown. The purpose of this study is to elucidate the effect of HER3 in radiotherapy and to assess whether HER3 could be a potential target for radiosensitivity. We used retroviruses to construct stable low expression of HER3 in MCF-7 and ZR75-1cells. The CCK-8 assay was used to observe proliferation. Colony-forming assay was used to detect radiosensitivity. Flow cytometry was used to observe the cell cycle and apoptosis. Immunofluorescence assay was used to detect the number of γH2AX foci in the nucleus with or without ionizing radiation (IR). Western blot analysis was used to verify the change of relative proteins. Nude mice were used to observe tumor growth in vivo. In our study, silencing HER3 reduced cell proliferation and clone formation ability after IR, so silencing HER3 increased the sensitivity of luminal A breast cancer cells to radiotherapy. In terms of radiosensitivity mechanisms, it is suggested that the silencing of HER3 enhanced IR-induced DNA damage, reduced DNA repair, and increased apoptosis and G2 /M arrest. In addition, silencing HER3 combined with IR clearly inhibited the transplanted tumor growth in vivo. Therefore, we concluded that HER3 played a role in radiotherapy resistance. Silencing HER3 increased the radiosensitivity of luminal A breast cancer cells and HER3 could be a potential target for radiosensitivity.
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- 2018
46. Reduced risk of breast cancer associated with recreational physical activity varies by HER2 status.
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Ma, Huiyan, Xu, Xinxin, Ursin, Giske, Simon, Michael S., Marchbanks, Polly A., Malone, Kathleen E., Lu, Yani, McDonald, Jill A., Folger, Suzanne G., Weiss, Linda K., Sullivan‐Halley, Jane, Deapen, Dennis M., Press, Michael F., and Bernstein, Leslie
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- *
BREAST cancer risk factors , *RECREATION , *HER2 protein , *ESTROGEN receptors , *PROGESTERONE receptors , *LOGISTIC regression analysis , *CALORIC expenditure , *BIOMARKERS - Abstract
Convincing epidemiologic evidence indicates that physical activity is inversely associated with breast cancer risk. Whether this association varies by the tumor protein expression status of the estrogen receptor ( ER), progesterone receptor ( PR), human epidermal growth factor receptor 2 ( HER2), or p53 is unclear. We evaluated the effects of recreational physical activity on risk of invasive breast cancer classified by the four biomarkers, fitting multivariable unconditional logistic regression models to data from 1195 case and 2012 control participants in the population-based Women's Contraceptive and Reproductive Experiences Study. Self-reported recreational physical activity at different life periods was measured as average annual metabolic equivalents of energy expenditure [ MET]-hours per week. Our biomarker-specific analyses showed that lifetime recreational physical activity was negatively associated with the risks of ER-positive ( ER+) and of HER2-negative ( HER2−) subtypes (both Ptrend ≤ 0.04), but not with other subtypes (all Ptrend > 0.10). Analyses using combinations of biomarkers indicated that risk of invasive breast cancer varied only by HER2 status. Risk of HER2-breast cancer decreased with increasing number of MET-hours of recreational physical activity in each specific life period examined, although some trend tests were only marginally statistically significant (all Ptrend ≤ 0.06). The test for homogeneity of trends ( HER2- vs. HER2+ ) reached statistical significance only when evaluating physical activity during the first 10 years after menarche ( Phomogeneity = 0.03). Our data suggest that physical activity reduces risk of invasive breast cancers that lack HER2 overexpression, increasing our understanding of the biological mechanisms by which physical activity acts. [ABSTRACT FROM AUTHOR]
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- 2015
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47. BTG2 as a tumor target for the treatment of luminal A breast cancer.
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Wang, Runzhi, Wang, Ronghua, Tian, Jinjun, Wang, Jian, Tang, Huaxiao, Wu, Tao, and Wang, Hui
- Subjects
- *
HORMONE receptor positive breast cancer , *BREAST cancer , *EPIDERMAL growth factor receptors , *TUMOR treatment , *BRCA genes , *CANCER cell proliferation - Abstract
As one of the most common breast cancer subtypes, luminal A breast cancer is sensitive to endocrine-based therapy and insensitive to chemotherapy. Patients with luminal A subtype of breast cancer have a relatively good prognosis compared with that of patients with other subtypes of breast cancer. However, with the increased incidence in endocrine resistance and severe side effects, simple endocrine therapy has become unsuitable for the treatment of luminal A breast cancer. Therefore, identifying novel therapeutic targets for luminal A breast cancer may accelerate the development of an effective therapeutic strategy. The bioinformatical analysis of the current study, which included KEGG and GO analyses of the GSE20437 dataset containing 24 healthy and 18 breast cancer tissue samples, identified key target genes associated with breast cancer. Moreover, survival analysis results revealed that a low expression of BTG2 was significantly associated with the low survival rate of patients with breast cancer, indicated that B-cell translocation gene 2 (BTG2) may be a potential target in breast cancer. However, BTG2 may be cancer type-dependent, as overexpression of BTG2 has been demonstrated to suppress the proliferation of pancreatic and lung cancer cells, but promote the proliferation of bladder cancer cells. Since the association between BTG2 and luminal A-subtype breast cancer remains unclear, it is important to understand the biological function of BTG2 in luminal A breast cancer. Based on the expression levels of estrogen receptor, progesterone receptor and human epidermal growth factor receptor, MCF-7 cells were selected in the present study as a luminal A breast cancer cell type. MTT, Transwell invasion and wound healing assays revealed that overexpression of BTG2 suppressed the levels of MCF-7 cell proliferation, migration and invasion. In addition, the downregulation of BTG2 at the mRNA and protein level was also confirmed in luminal A breast tumor tissue, which was consistent with the results in vitro. These results indicated that BTG2 may act as an effective target for the treatment of luminal A breast cancer. [ABSTRACT FROM AUTHOR]
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- 2022
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48. Identification of key genes unique to the luminal A and basal-like breast cancer subtypes via bioinformatic analysis
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Zhongxian Li, Yucheng Ji, Wei Liang, Rong Jia, Yujie Weng, Ying Liang, and Pengfei Ning
- Subjects
0301 basic medicine ,Bioinformatics ,lcsh:Surgery ,Kinesins ,Luminal a breast cancer ,Breast Neoplasms ,Cell Cycle Proteins ,Protein Serine-Threonine Kinases ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Text mining ,Neoplasm genes ,Surgical oncology ,Gene expression ,CDC2-CDC28 Kinases ,medicine ,Humans ,Protein Interaction Maps ,KEGG ,skin and connective tissue diseases ,Gene ,business.industry ,Research ,Intracellular Signaling Peptides and Proteins ,Computational Biology ,Basal-like breast cancer ,lcsh:RD1-811 ,Luminal a ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Precision medicine ,CD56 Antigen ,Receptors, Neurotransmitter ,Gene Expression Regulation, Neoplastic ,Gene Ontology ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Surgery ,business - Abstract
Background Breast cancer subtypes are statistically associated with prognosis. The search for markers of breast tumor heterogeneity and the development of precision medicine for patients are the current focuses of the field. Methods We used a bioinformatic approach to identify key disease-causing genes unique to the luminal A and basal-like subtypes of breast cancer. First, we retrieved gene expression data for luminal A breast cancer, basal-like breast cancer, and normal breast tissue samples from The Cancer Genome Atlas database. The differentially expressed genes unique to the 2 breast cancer subtypes were identified and subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. We constructed protein–protein interaction networks of the differentially expressed genes. Finally, we analyzed the key modules of the networks, which we combined with survival data to identify the unique cancer genes associated with each breast cancer subtype. Results We identified 1114 differentially expressed genes in luminal A breast cancer and 1042 differentially expressed genes in basal-like breast cancer, of which the subtypes shared 500. We observed 614 and 542 differentially expressed genes unique to luminal A and basal-like breast cancer, respectively. Through enrichment analyses, protein–protein interaction network analysis, and module mining, we identified 8 key differentially expressed genes unique to each subtype. Analysis of the gene expression data in the context of the survival data revealed that high expression of NMUR1 and NCAM1 in luminal A breast cancer statistically correlated with poor prognosis, whereas the low expression levels of CDC7, KIF18A, STIL, and CKS2 in basal-like breast cancer statistically correlated with poor prognosis. Conclusions NMUR1 and NCAM1 are novel key disease-causing genes for luminal A breast cancer, and STIL is a novel key disease-causing gene for basal-like breast cancer. These genes are potential targets for clinical treatment.
- Published
- 2020
49. ABTB2 Regulatory Variant as Predictor of Epirubicin-Based Neoadjuvant Chemotherapy in Luminal A Breast Cancer
- Author
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Peng Yuan, Xiating Peng, Danyi Zou, Yajie Gong, Jianbo Tian, Yang Yang, Xiang Cheng, Xiaoyang Wang, Li Ma, Chun-Han Lo, Yi Zhang, Lan Yang, Binghe Xu, Shufang Mei, Tieying Hou, Nanlin Hu, Rong Zhong, Wentong Li, Ying Zhu, Hong Zhang, and Jiang Chang
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,luminal A breast cancer ,medicine.medical_treatment ,Single-nucleotide polymorphism ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,single nucleotide polymorphism ,Internal medicine ,medicine ,Allele ,skin and connective tissue diseases ,Original Research ,Chemotherapy ,business.industry ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,030104 developmental biology ,epirubicin resistance ,Docetaxel ,Genetic marker ,030220 oncology & carcinogenesis ,Expression quantitative trait loci ,ABTB2 ,business ,Epirubicin ,medicine.drug ,neoadjuvant chemotherapy - Abstract
Background: Epirubicin combined with docetaxel is the cornerstone of neoadjuvant chemotherapy (NAC) for breast cancer. The efficacy of NAC for luminal A breast cancer patients is very limited, and single nucleotide polymorphism is one of the most important factors that influences the efficacy. Our study is aimed to explore genetic markers for the efficacy of epirubicin combined with docetaxel for NAC in patients with luminal A breast cancer. Methods: A total of 421 patients with two stages of luminal A breast cancer were enrolled in this study from 2 centers. Among them 231 patients were included in the discovery cohort and 190 patients are in the replication cohort. All patients received epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1, in a 21-day cycle, a cycle for 2-6 cycles. Before treatment, 2 ml of peripheral blood was collected from each patient to isolate genomic DNA. Fourteen functional variants potentially regulating epirubicin/docetaxel response genes were prioritized by CellMiner and bioinformatics approaches. Moreover, biological assays were performed to determine the effect of genetic variations on response to chemotherapy. Results: The patients carrying rs6484711 variant A allele suffered a poor response to epirubicin and docetaxel for NAC (OR = 0.37, 95% CI: 0.18-0.74, P = 0.005) in combined stage. Moreover, expression quantitative trait loci (eQTL) analyses and luciferase reporter assays revealed that rs6484711 A allele significantly increased the expression of ABTB2. Subsequent biological assays illustrated that upregulation of ABTB2 significantly reduced the apoptosis rate of breast cancer cells and enhanced the chemo-resistance to epirubicin. Conclusions: Our study demonstrated rs6484711 polymorphism regulating ABTB2 expression might predict efficacy to epirubicin based NAC in luminal A breast cancer patients. These results provided valuable information about potential role of genetic variations in individualized chemotherapy.
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- 2020
50. The molecular diversity of Luminal A breast tumors.
- Author
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Ciriello, Giovanni, Sinha, Rileen, Hoadley, Katherine, Jacobsen, Anders, Reva, Boris, Perou, Charles, Sander, Chris, and Schultz, Nikolaus
- Abstract
Breast cancer is a collection of diseases with distinct molecular traits, prognosis, and therapeutic options. Luminal A breast cancer is the most heterogeneous, both molecularly and clinically. Using genomic data from over 1,000 Luminal A tumors from multiple studies, we analyzed the copy number and mutational landscape of this tumor subtype. This integrated analysis revealed four major subtypes defined by distinct copy-number and mutation profiles. We identified an atypical Luminal A subtype characterized by high genomic instability, TP53 mutations, and increased Aurora kinase signaling; these genomic alterations lead to a worse clinical prognosis. Aberrations of chromosomes 1, 8, and 16, together with PIK3CA, GATA3, AKT1, and MAP3K1 mutations drive the other subtypes. Finally, an unbiased pathway analysis revealed multiple rare, but mutually exclusive, alterations linked to loss of activity of co-repressor complexes N-Cor and SMRT. These rare alterations were the most prevalent in Luminal A tumors and may predict resistance to endocrine therapy. Our work provides for a further molecular stratification of Luminal A breast tumors, with potential direct clinical implications. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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