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Amplification of human epidermal growth factor 2 receptor (HER2) and overexpression of estrogen receptor (ER) and/or progesterone receptor (PR) are key determinants in the treatment planning for human breast cancer (BC). Currently, targeted therapies for BC are focused mainly on these biomarkers. However, development of resistance to targeted drugs is almost unavoidable, emphasizing the importance of biochemical and pharmaceutical advances to improve treatment outcomes. To the best of our knowledge, the present study is the first to show functional crosstalk in vitro between HER2 and epithelial membrane protein 3 (EMP3), a tetraspan membrane protein, in human BC. EMP3 overexpression significantly promoted BC cell proliferation, invasion and migration by Transwell assays via epithelial-mesenchymal transition and transactivated the HER family, resulting in increased ER and PR expression in vitro . Knocking down EMP3 notably suppressed cell proliferation and migration and was accompanied by decreased expression of HER1‑HER3 and p‑SRC proteins. Suppression of EMP3 expression enhanced sensitivity of BC cells to trastuzumab in vitro . Xenograft experiments revealed decreased expression of HER1 and HER2 in stable EMP3‑knockdown cells, resulting in decreased tumor weight and size. In patients with BC, EMP3 overexpression was detected in 72 of 166 cases (43.4%), with 18 of 43 (41.9%) HER2‑amplified BC samples co‑expressing EMP3. Co‑expression of EMP3 and HER2 was positively associated with ER expression (P=0.028) and tended to be associated with nodal metastasis (P=0.085), however this was not significant. Taken together, the present results supported the potential of targeting EMP3 as a novel therapeutic strategy for human BC via co‑expression of HER2 and EMP3.

Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior. Despite multimodality therapy, local and distant relapse rates remain high. Therefore, neoadjuvant chemotherapy (NACT) is employed to improve the R0 resection rates and survival, but its benefits remain controversial. Herein, we investigate pathologic and molecular correlates to NACT-induced histologic response in a group of 29 breast AS, 4 primary and 25 radiation-associated (RA). The two NACT regimens applied were anthracycline- and non-anthracycline-based. The pathologic response grade was defined as: I: ≤ 50%, II: 51%-90%, III: 91%-99%, and IV: 100%. An additional 45 primary AS and 102 RA-AS treated by surgery alone were included for survival comparison. The genomic landscape was analyzed in a subset of cases and compared to a cohort of AS without NACT on a paired tumor-normal targeted DNA NGS platform. All patients were females, with a median age of 31 years in primary AS and 68 years in RA-AS. All surgical margins were negative in NACT group. The NACT response was evenly divided between poor (Grades I-II; n = 15) and good responders (Grades III-IV; n = 14). Mitotic count >10/mm 2 was the only factor inversely associated with pathologic response. By targeted NGS, all 10 post-NACT RA-AS demonstrated MYC amplification, while both primary AS harbored KDR mutations. TMB or other genomic alterations did not correlate with pathologic response. All four patients with Grade IV response remained free of disease. The good responders had a significantly better disease-specific survival (p = 0.04). There was no survival difference with NACT status or the NACT regimens applied. However, NACT patients with MYC-amplified tumors showed better disease-free survival (p = 0.04) compared to MYC-amplified patients without NACT. The overall survival of NACT group correlated with size >10 cm (p = 0.02), pathologic response (p = 0.04), and multifocality (p = 0.01) by univariate, while only size >10 cm (p = 0.03) remained significant by multivariate analysis., (© 2024 Wiley Periodicals LLC.)

Breast cancer (BC) represents one of the most prevalent malignant threats to women globally. Tumor relapse or metastasis is facilitated by BC stemness progression, contributing to tumorigenicity. Therefore, comprehending the characteristics of stemness progression and the underlying molecular mechanisms is pivotal for BC advancement. Hinokitiol (β-thujaplicin), a tropolone-related compound abundant in the heartwood of cupressaceous plants, exhibits antimicrobial activity. In our study, we employed three BC cell lines (MDA-MB-231, MCF-7, and T47D) to assess the expression of stemness-, apoptosis-, and autophagy-related proteins. Hinokitiol significantly reduced the viability of cancer cells in a dose-dependent manner. Furthermore, we observed that hinokitiol enhances apoptosis by increasing the levels of cleaved poly-ADP-ribose polymerase (PARP) and phospho-p53. It also induces dysfunction in autophagy through the upregulation of LC3B and p62 protein expression. Additionally, hinokitiol significantly suppressed the number and diameter of cancer cell line spheres by reducing the expression of cluster of differentiation44 (CD44) and key transcription factors. These findings underscore hinokitiol's potential as a therapeutic agent for breast cancer, particularly as a stemness-progression inhibitor. Further research and clinical studies are warranted to explore the full therapeutic potential of hinokitiol in the treatment of breast cancer.

Overexpression of the hypoxia-induced transmembrane enzyme carbonic anhydrase IX (CA9) has been associated with poor prognosis and chemoresistance in aggressive breast cancer. This study aimed to investigate the involvement of CA9 in the anti-tumor activity of para-toluenesulfonamide (PTS) and elucidate its mechanism of action against breast cancer both in vitro and in vivo. MCF-7 and MDA-MB-231 breast cancer cells were treated with PTS or subjected to hypoxic conditions using cobalt chloride (CoCl 2 ), with acetazolamide serving as a positive control. Additionally, 4T1 breast cancer cell allograft mice were co-treated with PTS and α-programmed cell death 1 (αPD-1) monoclonal antibody for one month. The results demonstrated that PTS effectively reduced cell viability and reversed migration ability in MCF-7 and MDA-MB-231 cells under CoCl 2 -induced hypoxia. Furthermore, PTS upregulated the expression of apoptosis-related proteins and downregulated CA9, hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) proteins, possibly through modulation of p38 MAPK and ERK1/2 phosphorylated proteins. In the animal model, PTS100 inhibited tumor growth and lung metastasis in mammary tumor allograft mice, exhibiting synergistic effects when combined with αPD-1 therapy. Collectively, our findings suggest that PTS inhibits breast cancer growth and metastasis through the p38 MAPK/ERK1/2 pathway. Moreover, PTS may have the potential to prevent the development of resistance to αPD-1 therapy in breast cancer., Competing Interests: Declaration of Competing Interest We confirm that there are no known conflicts of interest associated with this publication and that there have been no significant financial supports for this work that could have influenced the outcome., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an immune checkpoint and regulates the immune function of T cells. However, previous findings regarding the association of CTLA-4 polymorphisms and breast cancer remain inconclusive. Therefore, we performed a meta-analysis to investigate the potential effects of five polymorphisms (-1722 T/C, -1661 A/G -318 C/T, +49 A/G, and CT60 A/G) in the CTLA-4 gene on breast cancer susceptibility., Methods: Relevant literatures were systematically searched through electronic databases including PubMed, EMBASE, and Web of Science up to October 10, 2021. Available data were extracted and odds ratios (ORs) with 95% confidence intervals were used to estimate the pooling effect size. The Newcastle-Ottawa Scale was applied for assessing the quality of included studies. We conducted subgroup analyses based on ethnicity and control sources to explore levels of heterogeneity. Moreover, sensitivity analysis and publication bias were assessed., Results: Finally, a total of 12 eligible studies regarding CTLA-4 polymorphisms and breast cancer were included. For overall analyses, only the +49 A/G polymorphism was significantly associated with breast cancer under allelic (OR = 1.19), dominant (OR = 1.27), and recessive (OR = 1.27) models. Ethnicity-based subgroup analysis found that the +49 A/G polymorphism has a significant risk (OR = 2.03) of breast cancer under the recessive model in the non-Asian population. Studies with hospital-based controls showed that the +49 A/G polymorphism has significant breast cancer risks under allelic (OR = 1.44), dominant (OR = 1.86), and recessive (OR = 1.60) models. In addition, those with population-based controls found that -1722 T/C polymorphism has a significant breast cancer risk under allelic (OR = 1.19) and dominant (OR = 1.26) models., Conclusion: This meta-analysis suggested that CTLA-4 + 49 A/G polymorphism may significantly associate with breast cancer susceptibility. Future studies containing various populations are helpful for evaluating the impacts of CTLA-4 polymorphisms on breast cancer susceptibility., Competing Interests: Conflicts of interest: Dr. Shih-Hwa Chiou, an editorial board member at the Journal of the Chinese Medical Association, had no role in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article, (Copyright © 2023, the Chinese Medical Association.)

HOTAIR is a 2.2-kb long noncoding RNA (lncRNA) whose dysregulation has been linked to oncogenesis, defects in pattern formation during early development, and irregularities during the process of epithelial-to-mesenchymal transition (EMT). However, the oncogenic transformation determined by HOTAIR in vivo and its impact on chromatin dynamics are incompletely understood. Here, we generate a transgenic mouse model with doxycycline-inducible expression of human HOTAIR in the context of the MMTV-PyMT breast cancer-prone background to systematically interrogate the cellular mechanisms by which human HOTAIR lncRNA acts to promote breast cancer progression. We show that sustained high levels of HOTAIR over time increased breast metastatic capacity and invasiveness in breast cancer cells, promoting migration and subsequent metastasis to the lung. Subsequent withdrawal of HOTAIR overexpression reverted the metastatic phenotype, indicating oncogenic lncRNA addiction. Furthermore, HOTAIR overexpression altered both the cellular transcriptome and chromatin accessibility landscape of multiple metastasis-associated genes and promoted EMT. These alterations are abrogated within several cell cycles after HOTAIR expression is reverted to basal levels, indicating an erasable lncRNA-associated epigenetic memory. These results suggest that a continual role for HOTAIR in programming a metastatic gene regulatory program. Targeting HOTAIR lncRNA may potentially serve as a therapeutic strategy to ameliorate breast cancer progression., Competing Interests: QM, LY, KT, GW, YZ, UL, QS, LZ, CY, HJ, FZ, RL, MT, JC, IL, HZ, LL No competing interests declared, HC Reviewing editor, eLife, (© 2022, Ma, Yang, Tolentino et al.)

About 70% of cases of breast cancer are compromised by Estrogen-positive breast cancer. Through its regulation of several processes, including cell proliferation, cell cycle progression, and apoptosis, Estrogen signaling plays a pivotal role in the genesis and progression of this particular kind of breast cancer. One of the best treatment strategies for treating Estrogen-positive breast cancer is blocking Estrogen signaling. However, patients' treatment failure is mainly caused by the emergence of resistance and metastases, necessitating the development of novel therapeutic targets. Numerous studies have shown long noncoding RNAs (lncRNAs) to play a role in Estrogen-mediated carcinogenesis. These lncRNAs interact with co-regulators and the Estrogen signaling cascade components, primarily due to Estrogen activation. Vimentin and E-cadherin are examples of epithelial-to-mesenchymal transition markers, and they regulate genes involved in cell cycle progression, such as Cyclins, to affect the growth, proliferation, and metastasis of Estrogen-positive breast cancer. Furthermore, a few of these lncRNAs contribute to developing resistance to chemotherapy, making them more desirable targets for enhancing results. Thus, to shed light on the creation of fresh approaches for treating this cancer, this review attempts to compile recently conducted studies on the relationship between lncRNAs and the advancement of Estrogen-positive breast cancer., (© 2024 John Wiley & Sons Ltd.)

Objective: To validate and use the Chinese Version of the M. D. Anderson Symptom Inventory (MDASI-C) to assess the symptom burden of breast cancer patients in China., Methods: A total of 342 breast cancer patients in China participated in this study. Their symptoms were investigated with the MDASI-C from November 2020 to February 2021, and the reliability and validity of this tool were evaluated, respectively. Cluster analysis and correlation analysis were also performed., Results: The Cronbach's alpha coefficient values of the symptom and interference items were 0.827 and 0.880, respectively. Construct validity revealed a four-factor structure. The Kaiser-Meyer-Olkin value was 0.760. The Karnofsky Performance Status, treatment phase, and cancer stage of the patients were grouped, and the differences of scores within the groups were significant. In addition, the employment status, education level, and age of the patients were significantly correlated with the symptoms. The correlation analysis of the education level of the patients showed that most of the symptoms and interference items were reduced as the education level was increased. The top three symptoms were disturbed sleep (3.10±2.52), difficulty remembering (2.54±2.30), and fatigue (2.24±2.13). The clinical and biochemical indicators such as body mass index and neutral granulocyte lymphocyte ratio had effects on many symptoms. As the patients' BMI increased, the patients' pain, disturbed sleep, and difficulty remembering were aggravated, and numbness was alleviated., Conclusion: The MDASI-C is a reliable and effective assessment tool to evaluate patients with breast cancer in China. The symptoms are related to many clinical and biochemical indicators., (© 2022. Huazhong University of Science and Technology.)

The therapeutic efficacy of methoxypolyethylene glycol (mPEG)-coated nanomedicines in solid tumor treatment is hindered by tumor-associated fibroblasts (TAFs), which promote tumor progression and form physical barriers. We developed an anti-HER2/anti-FAP/anti-mPEG tri-specific antibody (TsAb) for one-step conversion of mPEG-coated liposomal doxorubicin (Lipo-Dox) to immunoliposomes, which simultaneously target HER2 + breast cancer cells and FAP + TAFs. The non-covalent modification did not adversely alter the physical characteristics and stability of Lipo-Dox. The TsAb-Lipo-Dox exhibited specific targeting and enhanced cytotoxicity against mono- and co-cultured HER2 + breast cancer cells and FAP + TAFs, compared to bi-specific antibody (BsAb) modified or unmodified Lipo-Dox. An in vivo model of human breast tumor containing TAFs also revealed the improved tumor accumulation and therapeutic efficacy of TsAb-modified mPEGylated liposomes without signs of toxicity. Our data indicate that arming clinical mPEGylated nanomedicines with the TsAb is a feasible and applicable approach for overcoming the difficulties caused by TAFs in solid tumor treatment.

Although alterations in chromatin structure are known to exist in tumors, how these alterations relate to molecular phenotypes in cancer remains to be demonstrated. Multi-omics profiling of human tumors can provide insight into how alterations in chromatin structure are propagated through the pathway of gene expression to result in malignant protein expression. We applied multi-omics profiling of chromatin accessibility, RNA abundance, and protein abundance to 36 human thyroid cancer primary tumors, metastases, and patient-match normal tissue. Through quantification of chromatin accessibility associated with active transcription units and global protein expression, we identify a local chromatin structure that is highly correlated with coordinated RNA and protein expression. In particular, we identify enhancers located within gene-bodies as predictive of correlated RNA and protein expression, that is independent of overall transcriptional activity. To demonstrate the generalizability of these findings we also identify similar results in an independent cohort of human breast cancers. Taken together, these analyses suggest that local enhancers, rather than distal enhancers, are likely most predictive of cancer gene expression phenotypes. This allows for identification of potential targets for cancer therapeutic approaches and reinforces the utility of multi-omics profiling as a methodology to understand human disease., (© 2021. The Author(s).)

Breast fibroepithelial lesions (FELs) encompass the common fibroadenoma (FA) and relatively rare phyllodes tumour (PT); the latter entity is usually classified as benign, borderline or malignant. Intratumoural heterogeneity is frequently present in these tumours, making accurate histologic evaluation challenging. Despite their rarity, PTs are an important clinical problem due to their propensity for recurrence and, in the case of malignant PT, metastasis. Surgical excision is the mainstay of management. Recent work has uncovered myriad genetic alterations in breast FELs. In this study, exome sequencing was performed on seven cases of morphologically heterogeneous breast FELs, including FAs, PTs of all grades, and a case of metaplastic spindle cell carcinoma arising in PT, in order to elucidate their intratumoural genetic repertoire. Gene mutations identified encompassed cell signalling, tumour suppressor, DNA repair and cell cycle regulating pathways. Mutations common to multiple tumour regions generally showed higher variant allele frequency. Frequent mutations included MED12, TP53, RARA and PIK3CA. Histological observations of increased cellular density and pleomorphism correlated with mutational burden. Phylogenetic analyses revealed disparate pathways of possible tumour progression. In summary, histological heterogeneity correlated with genetic changes in breast FELs.

Fibroepithelial tumours are biphasic neoplasms of the breast comprising the common benign fibroadenomas and the less common phyllodes tumours (PTs), which have recurrent potential. PTs are classified into benign, borderline or malignant, based on five histopathological criteria, with malignant PTs having the highest metastatic capability. Accurate diagnosis can be challenging due to the subjective assessment of histopathological parameters. Fibroadenomas bear morphological similarities to benign PTs, while borderline and malignant PTs can sometimes be difficult to distinguish from other spindle cell tumours of the breast. From clonality studies to whole-genome sequencing, much research has been conducted to elucidate the molecular pathogenesis of fibroepithelial tumours, which, in turn, have allowed leveraging the findings for diagnostic applications, including grading of PTs. The most noteworthy discovery was of recurrent MED12 mutations in both fibroadenomas and PTs. Subsequent studies also uncovered relatively frequent genetic mutations in TERT promoter and RARA A customised panel of 16 most frequently mutated genes in fibroepithelial tissues has been compiled previously and has contributed to resolving a few diagnostic dilemmas. This review will introduce the 16 genes and focus on the top three that are most frequently mutated in fibroepithelial tumours: MED12 , TERT , and RARA ., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Breast cancer (BC) is the most abundant and aggressive cancer that impacts millions of women with poorly understood mechanisms. Here, we aimed to investigate the function of LINC01806 in BC development. Human BC tissues and nearby normal specimens were taken from diagnosed BC patients. The expression levels of LINC01806, miR-1286, ZEB1, and EMT-related markers were evaluated by qRT-PCR and western blotting. FISH was used to visualize the subcellular localization of LINC01806. The viability, proliferation, migration and invasion capacities of BC cells were assessed by MTT, colony formation, and transwell assays. Interactions among LINC01806, miR-1286 and ZEB1 were validated by dual luciferase assay. The unpaired Student t-test (for two groups) or one-way ANOVA following with Tukey post-hoc test (for more than three groups) was employed for statistical analysis. LINC01806 level was elevated in BC tissues. Knockdown of LINC01806 suppressed EMT process and BC cell proliferation, migration, and invasion. LINC01806 co-localized and directly bound with miR-1286 in the cytoplasm. MiR-1286 inhibitor blocked the effects of LINC01806 knockdown on BC cell EMT, proliferation and migration. MiR-1286 targeted ZEB1 and overexpression of ZEB1 blocked the regulatory functions of miR-1286 mimics in BC. LINC01806 facilitates EMT and accelerates BC cell proliferation, migration, and invasion via acting as miR-1286 sponge to disinhibit ZEB1 expression., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Long noncoding RNAs (lncRNAs) play a role in the emergence and progression of several human tumors, including luminal B breast cancer (BC). The biological functions and potential mechanisms of lncRNA myocardial infarction-associated transcripts (MIAT) in luminal B BC, on the contrary, are unknown. In this work, we used UALCAN database analysis to find high expression of lncRNA MIAT in luminal BC tissues and also confirmed high levels of lncRNA MIAT expression in luminal B BC tissues and cells. In vitro knockdown of MIAT inhibited the proliferation, migration, and invasion of BT474 cells. In addition, we found that miR-150-5p levels were significantly reduced in luminal B BC specimens and cells, and miR-150-5p levels were significantly increased when MIAT was knocked down. And TIMER database analysis showed that MIAT was positively associated with PDL1. Through bioinformatic tools and in vitro experiments, lncRNA MIAT could function as a competitive endogenous RNA (CeRNA) to further regulate programmed cell death ligand 1 (PDL1) expression by directly sponging miR-150-5p. In conclusion, our data suggest that MIAT, an oncogene, may sponge miR-150-5p to regulate PDL1 expression and affect proliferation, migration, and invasion in luminal B BC in vitro., (© 2023. The Author(s), under exclusive licence to Institute of Plant Genetics Polish Academy of Sciences.)

Alterations in glycosylation are associated with breast tumor formation and progression. Nevertheless, the specific functions and mechanisms of the human major UDP-galactose transporter-encoding gene solute carrier family 35 member A2 (SLC35A2) in breast invasive carcinoma (BRCA) have not been fully determined. Here, we report that SLC35A2 promotes BRCA progression by activating extracellular signal regulated kinase (ERK). SLC35A2 expression and prognosis-predictive significance in pan-cancer were evaluated using public databases. The upstream non-coding RNAs (ncRNAs) of SLC35A2 were analyzed, and their expression and regulations were validated in breast tissues and cell lines by a quantitative PCR and dual-luciferase assays. We used bioinformatic tools to assess the link between SLC35A2 expression and immune infiltration and performed immunohistochemistry for validation. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine, transwell, flow cytometer and western blotting were used to assess the proliferation, motility, cell cycle and apoptosis of BRCA cells in vitro. The xenograft models were constructed to assess the effect of SLC35A2 on BRCA tumor growth in vivo. The results indicated that SLC35A2 expression was upregulated and linked to an unfavorable prognosis in BRCA. The most likely upstream ncRNA-associated pathway of SLC35A2 in BRCA was the AC074117.1/hsa-let-7b-5p axis. SLC35A2 expression had positive correlations with the presence of Th2 cells, regulatory T cells and immune checkpoints. Knockdown of SLC35A2 could reduce BRCA cell proliferation, motility, and cause G2/M arrest and cell apoptosis via ERK signaling. Moreover, ERK activation can rescue the inhibitory effects of knockdown SLC35A2 in BRCA. In conclusion, AC074117.1/hsa-let-7b-5p axis-mediated high expression of SLC35A2 acts as a tumor promoter in BRCA via ERK signaling, which provides a potential target for BRCA treatment., (© 2023 Federation of European Biochemical Societies.)

Background: Oestrogen receptor (ER) signalling-dependent cancer cell growth is one of the major features of ER-positive breast cancer (BC). Inhibition of ER function is a standard and effective treatment for ER-positive tumours; however, ~20% of patients with ER-positive BC experience early or late recurrence. In this study, we examined intertumour heterogeneity from an epigenetic perspective based on the hypothesis that the intrinsic difference in epigenetic states around ER signalling pathway underlies endocrine therapy resistance., Methods: We performed transposase-accessible chromatin sequencing (ATAC-seq) analysis of 42 BC samples, including 35 ER-positive(+) human epidermal growth factor receptor 2 (HER2)-negative(-) and 7 triple-negative tumours. We also reanalysed ATAC-seq data of 45 ER + /HER2 - tumours in the Cancer Genome Atlas (TCGA) BC cohort to validate our observations., Results: We conducted a comprehensive analysis of cis-regulatory elements (CREs) using ATAC-seq, identifying three subgroups based on chromatin accessibility profiles. We identified a subgroup of ER-positive BCs with a distinctive chromatin accessibility pattern including reduced accessibility to ER-responsive elements (EREs). The same subgroup was also observed in TCGA BC cohort. Despite the reduced accessibility to EREs, the expression of ER and potential ER target genes were not decreased in these tumours., Conclusion: Our findings highlight the existence of a subset of ER-positive BCs with unchanged ER expression but reduced EREs accessibility that cannot be distinguished by conventional immunostaining for ER. Future studies should determine whether these tumours are associated with resistance to endocrine therapy., (© 2023. The Author(s).)

Background: High Snail expression is known as a poor prognostic factor in breast cancer. However, its prognostic impact for breast cancer with different molecular subtypes is still controversial., Methods: Snail expression was examined by immunohistochemistry in tissue microarray slides of 85 corresponding tumor-adjacent normal (CTAN) and 247 breast invasive ductal carcinoma (IDC) tissues. Multivariable Cox regression analysis was used to assess the impact of Snail expression on survival rate by different molecular subtypes of breast IDC patients., Results: The level of Snail expression in IDC tumor tissues was significantly higher than that in CTAN tissues. Moreover, high Snail expression had direct impacts on poor disease specific survival (DSS) and disease-free survival (DFS) in breast IDC patients with human epidermal growth factor receptor 2 (HER2)-positive and human epidermal growth factor receptor (EGFR)-positive statuses as well as the HER2 intrinsic subtype. Additionally, breast IDC patients with a combination of three prognostic factors, including high Snail expression and HER2-positive and EGFR-positive statuses, had much poor DSS and DFS with a statistically significant linear trend., Conclusion: High Snail expression could predict a poor prognosis for breast IDC patients with HER2/EGFR-positive subtypes., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Long non-coding RNAs (lncRNAs) have been found to play important roles in occurrence, development, and metastasis of various tumors. We aimed to screen long non-coding RNAs (lncRNAs) that promote invasion and metastasis of breast cancer cells under hypoxia, and investigate the relationship between lncRNA expression and clinicopathological features and prognosis in invasive breast cancer., Methods: LncRNA microarray was used to screen the differentially expressed lncRNAs in MCF7, MDA-MB-231, and SKBR3 breast cancer cell lines cultured under normoxia and hypoxia, respectively. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to verify the microarray results. CCK8 and Transwell experiments were performed to identify the lncRNA that promote proliferation, migration, and invasion of breast cancer cells. Expression of the lncRNA and HIF-1α in invasive breast cancer was detected by RNAscope and immunohistochemistry, respectively. Correlation between the lncRNA expression and baseline characteristics was analyzed. Prognostic value of the lncRNA was evaluated using univariate and multivariate Cox regression., Results: Expression of lncRNA TCONS&#95;I2&#95;00001955 in all the three breast cancer cells was increased under hypoxia. Overexpression of TCONS&#95;I2&#95;00001955 significantly enhanced proliferation, migration, and invasion of SKBR3 cells. Positive expression of TCONS&#95;I2&#95;00001955 was associated with recurrence, metastasis, and high expression of HIF-1α (P < 0.05), and it was an independent risk factor for poor disease-free survival of breast cancer., Conclusion: Hypoxia-induced lncRNA TCONS&#95;I2&#95;00001955 was associated with aggressive feature and poor prognosis of breast cancer., (© 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Noncoding mutations in cancer genomes are frequent but challenging to interpret. PVT1 encodes an oncogenic lncRNA, but recurrent translocations and deletions in human cancers suggest alternative mechanisms. Here, we show that the PVT1 promoter has a tumor-suppressor function that is independent of PVT1 lncRNA. CRISPR interference of PVT1 promoter enhances breast cancer cell competition and growth in vivo. The promoters of the PVT1 and the MYC oncogenes, located 55 kb apart on chromosome 8q24, compete for engagement with four intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to regulate pause release of MYC transcription. PVT1 undergoes developmentally regulated monoallelic expression, and the PVT1 promoter inhibits MYC expression only from the same chromosome via promoter competition. Cancer genome sequencing identifies recurrent mutations encompassing the human PVT1 promoter, and genome editing verified that PVT1 promoter mutation promotes cancer cell growth. These results highlight regulatory sequences of lncRNA genes as potential disease-associated DNA elements., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The isocitrate dehydrogenase (IDH) gene family expresses key functional metabolic enzymes in the Krebs cycle and mediates the epigenetic reprogramming, which serves as an important biomarker of breast cancer. However, the expression levels of the IDH protein and their biological function in human breast cancer remain largely unknown., Methods: In this study, the clinical impact of IDH1 expression on the progression and prognosis of breast cancer was evaluated using immunohistochemistry assay (IHC) of the corresponding tumor-adjacent normal, ductal carcinoma in situ (DCIS), and invasive ductal carcinoma (IDC) tissues from 309 patients with breast ductal carcinoma. The relationship between microRNA (miRNA) and IDH1 were examined by a bioinformatics approach, western blot and reporter assay. The biological functions of IDH1 were examined in breast cancer cells with IDH1 knockdown, including proliferation, migration and invasion., Results: The present findings revealed that the mRNA and protein expression levels of IDH1 were both significantly lower in breast cancer tissues than in adjacent normal tissues. A low expression level of IDH1 in breast cancer significantly correlated with advanced stage (p = 0.012), lymph node metastasis (p = 0.018), and poor disease-specific survival (DSS) (adjusted hazard ratio (AHR), 1.57, 95% confidence interval (CI), 1.08-2.30; p = 0.02). Furthermore, oncogenic miR-32 and miR-92b were identified to suppress IDH1 expression, leading to the inhibition of cell migration and invasion. We further explored whether reduced expression of IDH1 significantly increases snail expression by activating HIFα (hypoxia-inducible factor-1 alpha) and NFκB (nuclear factor kappa B) signaling. Multivariate Cox regression analysis revealed that the combination of low IDH1 and high snail expression could be an independent risk factor for shorter DSS (AHR, 2.34; 95% CI, 1.32-4.16; p = 0.004) and shorter disease-free survival (AHR, 2.50; 95% CI, 1.39-4.50; p = 0.002) in patients with breast cancer., Conclusion: Our findings revealed that a IDH1 low /Snail high molecular signature could serve as an independent biomarker for poor prognosis in breast cancer.

Background: Tamoxifen is a first-line endocrine agent and is often used to treat estrogen receptor-positive (ER+) breast cancer. Unfortunately, approximately 30-40% of patients who received tamoxifen therapy experience recurrence or progression to a fatal advanced stage due to tamoxifen resistance. However, the mechanisms of tamoxifen resistance remain unclear., Methods: The expression of lncRNA DLGAP1 antisense RNA 2 (DLGAP1-AS2) was detected by qPCR. The effect of DLGAP1-AS2 on tamoxifen resistance was evaluated by MTT, colony formation, TUNEL and flow cytometric assays. The mechanisms by which DLGAP1-AS2 regulates tamoxifen resistance were investigated through qPCR, RNA pull-down assays and RNA immunoprecipitation (RIP) assays., Results: Our results showed that DLGAP1-AS2 is significantly upregulated in breast cancer and that tamoxifen can induce DLGAP1-AS2 expression. Further investigation suggested that upregulation of DLGAP1-AS2 can increase cell viability and inhibit apoptosis, while downregulation of DLGAP1-AS2 results in the opposite effects. Mechanistically, DLGAP1-AS2 can bind to the AFF3 protein to inhibit its degradation, which further promotes ER signalling., Conclusions: Our research clarified that DLGAP1-AS2 promotes ER signalling to induce tamoxifen resistance and that targeting DLGAP1-AS2 might be a promising strategy to overcome tamoxifen resistance in breast cancer., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Epithelial-mesenchymal transition (EMT), a transdifferentiation program whereby epithelial cells acquire mesenchymal phenotype, is essential during embryonic development. EMT has also been implicated in cancer progression by conferring migratory and metastatic potential, as well as cell plasticity and stem cell like traits, to cancer cells. Metaplastic breast carcinoma (MBC) is a rare aggressive type of breast cancer characterized by the presence of heterologous elements, typically by the existence of epithelial and mesenchymal components. Phyllodes tumors (PTs) are uncommon fibroepithelial neoplasms consisting of epithelial and mesenchymal elements. Although various hypotheses have been proposed on the pathogenesis of these biphasic tumors, there is growing evidence supporting the theory that PTs and MBC could both correlate with cancer related EMT. This review summarizes the existing literature on the emerging role of EMT in the pathogenesis of MBC and PTs. Both malignant PTs and MBC are characterized by poor prognosis. Therefore, several anti-EMT targeting strategies such as blocking upstream signaling pathways, targeting the molecular drivers of EMT and targeting mesenchymal cells and the extracellular matrix, could potentially represent a promising therapeutic approach for patients suffering from these aggressive neoplasms., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Overactivated neddylation is considered to be a common event in cancer. Long non-coding RNAs (lncRNAs) can regulate cancer development by mediating post-translational modifications. However, the role of lncRNA in neddylation modification remains unclear., Methods: LncRNA cytochrome P450 family 1 subfamily B member 1 antisense RNA 1 (CYP1B1-AS1) expression in breast cancer tissues was evaluated by RT-PCR and TCGA BRCA data. Gain and loss of function experiments were performed to explore the role of CYP1B1-AS1 in breast cancer cell proliferation and apoptosis in vitro and in vivo. Luciferase assay, CHIP-qPCR assay, transcriptome sequencing, RNA-pulldown assay, mass spectrometry, RIP-PCR and Western blot were used to investigate the regulatory factors of CYP1B1-AS1 expression and the molecular mechanism of CYP1B1-AS1 involved in neddylation modification., Results: We found that CYP1B1-AS1 was down-regulated in breast cancer tissues and correlated with prognosis. In vivo and in vitro functional experiments confirmed that CYP1B1-AS1 inhibited cell proliferation and induced apoptosis. Mechanistically, CYP1B1-AS1 was regulated by the transcription factor, forkhead box O1 (FOXO1), and could be upregulated by inhibiting the PI3K/FOXO1 pathway. Moreover, CYP1B1-AS1 bound directly to NEDD8 activating enzyme E1 subunit 1 (NAE1) to regulate protein neddylation., Conclusion: This study reports for the first time that CYP1B1-AS1 inhibits protein neddylation to affect breast cancer cell proliferation, which provides a new strategy for the treatment of breast cancer by lncRNA targeting neddylation modification., (© 2023. The Author(s).)

Background: Hox transcript antisense RNA (HOTAIR) is considered an oncogene associated with the initiation and progression of many malignancies. Previous studies have examined the connection between HOTAIR SNPs rs4759314 and rs920778 for breast cancer (BC), getting variable results in multiple ethnicities. Therefore, this study was designed to evaluate the connection between these two SNPs and disease vulnerability, clinic-laboratory, and hormonal parameters, featuring status associations with the BC risk in an Egyptian woman sample., Methods and Results: In this case-control study, DNA was taken from the blood of 100 BC patients and 100 unrelated healthy Egyptian females. The characterization of rs4759314 was genotyped using the T-ARMS-PCR method and rs920778 using the SNP-RFLP technique for all participants. The frequency of the rs4759314 A > G variation revealed a statistically significant increase in BC risk with dominant (p = 0.013, OR = 1.592, 95% Cl = 1.105-2.293), co-dominant (p = 0.006, OR = 2.314, 95%Cl = 1.278-4.191) and overdominant (p = 0.002, OR = 2.571, 95% Cl = 1.430-4.624) genetic models. On the other hand, the rs920778 C > T polymorphism was not significantly associated with BC. ER/PR positivity with HER2 negativity was significantly associated with the AA genotype compared to the AG genotype. Otherwise, no significant associations between the two SNPs and clinical stage or hormonal features could be found. In conclusion, the rs4759314 A > G SNP in the HOTAIR gene is strongly associated with BC, which might warrant its determination among affected families for prevention and early treatment., (© 2023. The Author(s).)

Background: Despite major improvements in treatment of HER2-positive metastatic breast cancer (MBC), only few patients achieve complete remission and remain progression free for a prolonged time. The tumor immune microenvironment plays an important role in the response to treatment in HER2-positive breast cancer and could contain valuable prognostic information. Detailed information on the cancer-immune cell interactions in HER2-positive MBC is however still lacking. By characterizing the tumor immune microenvironment in patients with HER2-positive MBC, we aimed to get a better understanding why overall survival (OS) differs so widely and which alternative treatment approaches may improve outcome., Methods: We included all patients with HER2-positive MBC who were treated with trastuzumab-based palliative therapy in the Netherlands Cancer Institute between 2000 and 2014 and for whom pre-treatment tissue from the primary tumor or from metastases was available. Infiltrating immune cells and their spatial relationships to one another and to tumor cells were characterized by immunohistochemistry and multiplex immunofluorescence. We also evaluated immune signatures and other key pathways using next-generation RNA-sequencing data. With nine years median follow-up from initial diagnosis of MBC, we investigated the association between tumor and immune characteristics and outcome., Results: A total of 124 patients with 147 samples were included and evaluated. The different technologies showed high correlations between each other. T-cells were less prevalent in metastases compared to primary tumors, whereas B-cells and regulatory T-cells (Tregs) were comparable between primary tumors and metastases. Stromal tumor-infiltrating lymphocytes in general were not associated with OS. The infiltration of B-cells and Tregs in the primary tumor was associated with unfavorable OS. Four signatures classifying the extracellular matrix of primary tumors showed differential survival in the population as a whole., Conclusions: In a real-world cohort of 124 patients with HER2-positive MBC, B-cells, and Tregs in primary tumors are associated with unfavorable survival. With this paper, we provide a comprehensive insight in the tumor immune microenvironment that could guide further research into development of novel immunomodulatory strategies., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Purpose: The oncogenic factor ZNF217 promotes aggressive estrogen receptor (ER)+breast cancer disease suggesting that its inhibition may be useful in the clinic. Unfortunately, no direct pharmacological inhibitor is available. Dimethyl fumarate (DMF) exhibits anti-breast cancer activities, in vitro and in pre-clinical in vivo models. Its therapeutic benefits stem from covalent modification of cellular thiols such as protein cysteines, but the full profile of molecular targets mediating its anti-breast cancer effects remains to be determined., Methods: ER+breast cancer cells were treated with DMF followed by cysteine-directed proteomics. Cells with modulated ZNF217 levels were used to probe the efficacy of DMF., Results: Covalent modification of ZNF217 by DMF identified by proteomics was confirmed by using a DMF-chemical probe. Inhibition of ZNF217's transcriptional activity by DMF was evident on reported ZNF217-target genes. ZNF217 as an oncogene has been shown to enhance stem-like properties, survival, proliferation, and invasion. Consistent with ZNF217 inhibition, DMF was more effective at blocking these ZNF217-driven phenotypes in cells with elevated ZNF217 expression. Furthermore, partial knockdown of ZNF217 led to a reduction in DMF's efficacy. DMF's in vivo activity was evaluated in a xenograft model of MCF-7 HER2 cells that have elevated expression of ZNF217 and DMF treatment resulted in significant inhibition of tumor growth., Conclusion: These data indicate that DMF's anti-breast cancer activities in the ER+HER2+models, at least in part, are due to inhibition of ZNF217. DMF is identified as a new covalent inhibitor of ZNF217., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Currently, the prediction of breast cancer (BC) effectiveness to drug treatment is based on determining the expression level of steroid hormone receptors and human epidermal growth factor receptor type 2 (HER2). However, significant differences in individual response to drug treatment require the search for new predictive markers. Here, by comprehensively examining HIF-1α, Snail, and PD-L1 expression in BC tumor tissue, we demonstrate that high levels of these markers correlate with unfavorable factors of BC prognosis: the presence of regional and distant metastases and lymphovascular and perineural invasion. Analyzing the predictive significance of markers, we show that the most significant predictors of chemoresistant HER2-negative BC are a high PD-L1 level and a low Snail level, while in HER2-positive BC, only a high PD-L1 level is an independent predictor of chemoresistant BC. Our results suggest that using immune checkpoint inhibitors in these groups of patients may improve drug therapy effectiveness., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Development of drug resistance is a major factor limiting the continued success of cancer chemotherapy. To overcome drug resistance, understanding the underlying mechanism(s) is essential. We found that HOXC10 is overexpressed in primary carcinomas of the breast, and even more significantly in distant metastasis arising after failed chemotherapy. High HOXC10 expression correlates with shorter recurrence-free and overall survival in patients with estrogen receptor-negative breast cancer undergoing chemotherapy. We found that HOXC10 promotes survival in cells treated with doxorubicin, paclitaxel, or carboplatin by suppressing apoptosis and upregulating NF-κB Overexpressed HOXC10 increases S-phase-specific DNA damage repair by homologous recombination (HR) and checkpoint recovery in cells at three important phases. For double-strand break repair, HOXC10 recruits HR proteins at sites of DNA damage. It enhances resection and lastly, it resolves stalled replication forks, leading to initiation of DNA replication following DNA damage. We show that HOXC10 facilitates, but is not directly involved in DNA damage repair mediated by HR. HOXC10 achieves integration of these functions by binding to, and activating cyclin-dependent kinase, CDK7, which regulates transcription by phosphorylating the carboxy-terminal domain of RNA polymerase II. Consistent with these findings, inhibitors of CDK7 reverse HOXC10-mediated drug resistance in cultured cells. Blocking HOXC10 function, therefore, presents a promising new strategy to overcome chemotherapy resistance in breast cancer. Cancer Res; 76(15); 4443-56. ©2016 AACR., (©2016 American Association for Cancer Research.)

Purposes: To (1) determine the frequency and severity of hot flashes, (2) examine the associations between hot flash frequency and severity and quality of life, and (3) identify the predictors of hot flash activity in breast cancer survivors., Methods: The study used a cross-sectional design and mailed survey of 253 breast cancer survivors recruited from a cancer wellness clinic. Participants provided information regarding cancer history, hot flashes, pain intensity, sleep problems, physical functioning, and psychological functioning., Results: About half of the survivors reported at least one hot flash in the past 24 h (45%) or past week (52%). The average frequency of hot flashes was 1.9 in the past 24 h and 1.8 in the past week. Hot flash severity was usually mild or asymptomatic. However, participants with hot flashes reported significantly more sleep problems and higher pain severity than those reporting no hot flashes. Moreover, the severity of hot flashes was associated with more sleep problems, higher pain severity, and more psychological dysfunction. History of hormonal suppression therapy and younger age predicted hot flash activity in the study sample., Conclusions: In breast cancer survivors, hot flashes are common and are associated with unpleasant symptoms and poor quality of life. Research is needed to determine if treatments that reduce the frequency and severity of hot flashes in breast cancer survivors also result in improvements in symptoms such as sleep problems, pain, and psychological dysfunction., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aims: Juvenile fibroadenomas (JFA) are biphasic fibroepithelial lesions (FEL) usually occurring in adolescent female patients. Giant (G) JFA, like other FEL, may exhibit prominent pseudoangiomatous stromal hyperplasia (PASH)-like change. We sought to determine clinicopathological and molecular characteristics of GJFA with and without PASH., Methods and Results: Archives were searched for cases of GJFA (1985-2020). All were stained for androgen receptor (AR), beta-catenin, CD34 and progesterone receptor (PR). Cases were sequenced using a custom 16-gene panel - MED12 (exons 1 and 2), TERT promoter (-124C>T and -146Ctable>T), SETD2, KMT2D, RARA (exons 5-9), FLNA, NF1, PIK3CA (exons 10, 11 and 21), EGFR, RB1, BCOR, TP53, PTEN, ERBB4, IGF1R and MAP3K1. Twenty-seven GJFA from 21 female patients aged 10.1-25.2 years were identified. Size ranged from 5.2 to 21 cm. Two patients had multiple, bilateral and later recurrent GJFA. Thirteen (48%) cases showed prominent PASH-like stroma. All were positive for stromal CD34, negative for AR and beta-catenin and one case showed focal PR expression. Sequencing showed MAP3K1 and SETD2 mutations in 17 samples, with KMT2D, TP53 and BCOR aberrations in 10 (45%), 10 (45%) and seven (32%) cases, respectively. Tumours with a PASH-like pattern had higher prevalence of SETD2 (P = 0.004) and TP53 (P = 0.029) mutations, while those without PASH had more RB1 mutations (P = 0.043). MED12 mutation was identified in one case. TERT promoter mutation was observed in four (18%), including two recurrences., Conclusions: Gene mutations along more advanced phases of the proposed FEL pathogenetic pathway in GJFA are unusual, and suggest a mechanism for more aggressive growth in these tumours., (© 2023 John Wiley & Sons Ltd.)

This study was to explore the regulatory effect of long non-coding RNA LINC01559 on Docetaxel resistance in breast carcinoma (BCa) and its underlying mechanism. In the present study, we found that LINC01559 expression was elevated and LINC01559 overexpression facilitated docetaxel resistance in BCa cells. Moreover, it was revealed that the upregulation of LINC01559 in BCa cells was induced by FTO-mediated demethylation in an m6A-YTHDF2-dependent manner. Additionally, Dual-luciferase reporter assay confirmed the binding ability between LINC01559 and miR-1343-3p, and Pearson correlation analysis showed a negative correlation between them. Particularly, miR-1343-3p inhibition partly abolished the suppression on docetaxel resistance in BCa cells caused by LINC01559 knockdown. To sum up, FTO-mediated epigenetic upregulation of LINC01559 promoted cell resistance to Docetaxel in BCa by negatively regulating miR-1343-3p., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

A hallmark of many malignant tumors is dedifferentiated (immature) cells bearing slight or no resemblance to the normal cells from which the cancer originated. Tumor dedifferentiated cells exhibit a higher capacity to survive to chemo and radiotherapies and have the ability to incite tumor relapse. Inducing cancer cell differentiation would abolish their self-renewal and invasive capacity and could be combined with the current standard of care, especially in poorly differentiated and aggressive tumors (with worst prognosis). However, differentiation therapy is still in its early stages and the intrinsic complexity of solid tumor heterogeneity demands innovative approaches in order to be efficiently translated into the clinic. We demonstrate here that microRNA 203, a potent driver of differentiation in pluripotent stem cells (ESCs and iPSCs), promotes the differentiation of mammary gland tumor cells. Combining mouse in vivo approaches and both mouse and human-derived tridimensional organoid cultures, we report that miR-203 influences the self-renewal capacity, plasticity and differentiation potential of breast cancer cells and prevents tumor cell growth in vivo. Our work sheds light on differentiation-based antitumor therapies and offers miR-203 as a promising tool for directly confronting the tumor-maintaining and regeneration capability of cancer cells., (© 2023. BioMed Central Ltd., part of Springer Nature.)

This is a literature review describes Crohn's disease (CD) concomitant with breast cancer and summarizes possible common pathogenic mechanisms shared by the two diseases involving the IL-17 and NF-κB signaling pathways. Inflammatory cytokines including TNF-α and Th17 cells in CD patients can induce activation of the ERK1/2, NF-κB and Bcl-2 pathways. Hub genes are involved in the generation of cancer stem cells (CSCs) and are related to inflammatory mediators, including CXCL8, IL1-β and PTGS2, which promote inflammation and breast cancer growth, metastasis, and development. CD activity is highly associated with altered intestinal microbiota processes, including secretion of complex glucose polysaccharides by Ruminococcus gnavus colonies; furthermore, γ-proteobacteria and Clostridium are associated with CD recurrence and active CD, while Ruminococcaceae, Faecococcus and Vibrio desulfuris are associated with CD remission. Intestinal microbiota disorder promotes breast cancer occurrence and development. Bacteroides fragilis can produce toxins that induce breast epithelial hyperplasia and breast cancer growth and metastasis. Gut microbiota regulation can also improve chemotherapy and immunotherapy efficacy in breast cancer treatment. Intestinal inflammation can affects the brain through the brain-gut axis, which activates the hypothalamic‒pituitary‒adrenal (HPA) axis to induce anxiety and depression in patients; these effects can inhibit the antitumor immune responses of the immune system and promote breast cancer occurrence in patients with CD. There are few studies on the treatment of patients with CD concomitant with breast cancer, but published studies show three main strategies: new biological agents combined with breast cancer treatment methods, intestinal fecal bacteria transplantation, and dietary treatment., (© 2023. The Author(s).)

Organotellurium compounds are being well researched as potential candidates for their functional roles in therapeutic and clinical biology. Here, we report the in vitro anticancer and antibacterial activities of an AS101 analog, cyclic zwitterionic organotellurolate (IV) compound 2 [Te - {CH 2 CH(NH 3 + )COO}(Cl) 3 ]. Different concentrations of compound 2 were exposed to fibroblast L929 and breast cancer MCF-7 cell lines to study its effect on cell viability. The fibroblast cells with good viability confirmed the biocompatibility, and compound 2 also was less hemolytic on RBCs. A cytotoxic effect on MCF-7 breast cancer cell line investigated compound 2 to be anti-cancerous with IC50 value of 2.86 ± 0.02 µg/mL. The apoptosis was confirmed through the cell cycle phase arrest of the organotellurolate (IV) compound 2. Examination of the antibacterial potency compound 2 was done based on the agar disk diffusion, minimum inhibitory concentration, and time-dependent assay for the Gram-positive Bacillus subtilis and Gram-negative Pseudomonas putida. For both bacterial strains, tests were performed with the concentration range of 3.9-500 μg/mL, and the minimum inhibition concentration value was found to be 125 μg/mL. The time-dependent assay suggested the bactericidal activity of organotellurolate (IV) compound, 2 against the bacterial strains., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Pyruvate dehydrogenase kinase 1 (PDK1) is a widely known glycolytic enzyme, and some evidence showed that PDK1 promoted breast cancer by multiple approaches. However, very few lncRNAs have been identified to be associated with PDK1 in breast cancer in previous research. In this study, we found that lncRNA sprouty4-intron transcript 1 (SPRY4-IT1) was regulated by PDK1 with correlation analysis, and PDK1 upregulated SPRY4-IT1 remarkably in breast cancer cells, as PDK1 interacted with SPRY4-IT1 in the nucleus and significantly enhanced the stability of SRPY4-IT1. Furthermore, SPRY4-IT1 was highly expressed in breast cancer, significantly promoted the proliferation and inhibited apoptosis of breast cancer cells. In terms of mechanism, SPRY4-IT1 inhibited the transcription of NFKBIA and the expression of IκBα, thus promoting the formation of p50/p65 complex and activating NF-κB signaling pathway, which facilitated survival of breast cancer cells. Therefore, our finding reveals that PDK1/SPRY4-IT1/NFKBIA axis plays a crucial role that promoting tumor progression, and SPRY4-IT1 knockdown incombined with PDK1 inhibitor is promising to be a new therapeutic strategy in breast cancer., (© 2023 Wiley Periodicals LLC.)

DNA methylation at the 5 position of cytosine (5 mC) is an epigenetic hallmark in cancer. The 5 mC can be converted to 5-hydroxymethylcytosine (5 hmC) through a ten-eleven-translocation (TET). We investigated the impact of 5 mC, 5 hmC, TET1, and TET2 on tumorigenesis and prognosis of breast cancer. Immunohistochemistry was used to assess the levels of 5 mC, 5 hmC, TET1, and TET2 in the corresponding tumor adjacent normal (n = 309), ductal carcinoma in situ (DCIS, n = 120), and invasive ductal carcinoma (IDC, n = 309) tissues for 309 breast ductal carcinoma patients. 5 mC, 5 hmC, TET1-n, and TET2-n were significantly decreased during DCIS and IDC progression. In IDC, the decrease of 5 hmC was correlated with the cytoplasmic mislocalization of TET1 (p < 0.001) as well as poor disease-specific survival (DSS) (adjusted hazard ratio [AHR] 1.95, p = 0.003) and disease-free survival (DFS) (AHR 1.91, p = 0.006). The combined decrease of 5 mC and 5 hmC was correlated with worse DSS (AHR 2.19, p = 0.008) and DFS (AHR 1.99, p = 0.036). Stratification analysis revealed that the low level of 5 mC was associated with poor DSS (AHR 1.89, p = 0.044) and DFS (AHR 2.02, p = 0.035) for the ER/PR-positive subtype. Conversely, the low level of 5 hmC was associated with worse DSS (AHR 2.77, p = 0.002) and DFS (AHR 2.69, p = 0.006) for the ER/PR-negative subtype. The decreases of 5 mC, 5 hmC, TET1-n, and TET2-n were biomarkers of tumor development. The global reduction of 5 hmC was a poor prognostic factor for IDC, especially for ER/PR-negative subtype.

Depression has been hypothesized to be a risk factor of cancer, especially hormone-related cancers. However, few studies have been conducted with large enough sample size and sufficient follow-up period to rigorously estimate these associations. We aim to examine the relationship between depression and risk of registry-documented overall and hormone-related cancers. In this 19 year prospective cohort study of general population, 601,775 Koreans aged 30-64 years had a biennial medical evaluation by the National Health Insurance Service in either 1992 or 1994. Major and minor depression was ascertained by a 9-item depression questionnaire. At baseline, major depression was identified in 7.4% and 10.2% and minor depression in 19.3% and 21.4% in men and women, respectively. During the follow-up, 49,744 cancers were identified in men and 7860 in women. Prostate cancer in men was positively related to minor depression (HR 1.13, 95% CI 1.05, 1.23), and cervical cancer in women was inversely related to major depression (HR 0.90, 95% CI 0.83, 0.98) after adjusting for potential confounders. Regarding overall cancer, major depression was positively related to overall cancer in men (HR 1.04, 95% CI 1.00, 1.08) and inversely related in women (HR 0.90, 95% CI 0.83, 0.98). There was no association between breast cancer and depression. Different direction and magnitude of association among gender and cancer subtypes suggest different psycho-behavioral and biological pathways in which depression may affect later cancer development. Further studies on the association of depression and cancer and the underlying mechanisms should be conducted on specific cancer subtypes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Accumulating evidence has shown that long noncoding RNAs (lncRNAs) play a significant role in regulating gene expression and participating in the progression of various malignancies. In our study, by analyzing data from The Cancer Genome Atlas (TCGA), LINC00536 was found to be highly expressed in breast cancer (BC) tissues, but its function and clinical significance in BC are still unknown. Therefore, we aimed to explore the role and molecular mechanism of LINC00536 in BC. We collected human BC tissue specimens and validated that LINC00536 was overexpressed in BC tissues. Increased LINC00536 expression was associated with advanced TNM stage, larger tumor diameter, lymph node metastasis and poor prognosis in patients with BC. Univariate and multivariate Cox regression analyses showed that high LINC00536 expression was an independent prognostic risk factor for overall survival in BC patients. Furthermore, quantitative reverse transcription PCR (qRT-PCR) showed that LINC00536 was upregulated in BC cell lines. Then, we confirmed that LINC00536 silencing-inhibited BC cell proliferation, migration, and invasion and led to cell cycle arrest in vitro. Animal experiments showed that knockdown of LINC00536 expression suppressed tumorigenesis in vivo. Mechanistically, LINC00536 serves as a ceRNA for miR-214-5p, increasing the expression of ROCK1, which acts as a tumor promoter in BC. Rescue assays revealed that miR-214-5p inhibition or ROCK1 overexpression could neutralize the suppressive effects of LINC00536 knockdown on cell proliferation, migration and invasion. Our data indicated that LINC00536 accelerates BC progression by regulating the miR-214-5p/ROCK1 pathway, which might provide a new perspective to investigate the development process of BC., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Breast cancer, one of the most commonly diagnosed cancers worldwide, is a heterogeneous disease with high rates of recurrence and metastasis that contribute to its high mortality rate. Breast cancer stem cells (BCSCs) are a small but significant subset of heterogeneous breast cancer cells that possess stem cell characteristics such as self-renewal and differentiation abilities that may drive metastasis and recurrence. Long non-coding RNAs (lncRNAs) are a class of RNAs that are longer than 200 nucleotides in length and do not possess protein-coding properties. An increasing number of studies have shown that some lncRNAs are abnormally expressed in BCSCs, and have great biological significance in the occurrence, progression, invasion, and metastasis of various cancers. However, the importance of lncRNAs, as well as the molecular mechanisms that regulate and promote the stemness of BCSCs, are still poorly understood. In the current review, we aim to summarize recent studies that highlight the role of lncRNAs in tumor occurrence and progression through BCSCs. In addition, the utility of lncRNAs as biomarkers of breast cancer progression, and their potential use as therapeutic targets for treatment of breast cancer, will be discussed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

F1Fo ATP synthase is present in all organisms and is predominantly located on the inner membrane of mitochondria in eukaryotic cells. The present study demonstrated that ATP synthase and electron transport chain complexes were ectopically expressed on the surface of breast cancer cells and could serve as a potent anticancer target. We investigated the anticancer effects of the ATP synthase inhibitor citreoviridin on breast cancer cells through proteomic approaches and revealed that differentially expressed proteins in cell cycle regulation and in the unfolded protein response were functionally enriched. We showed that citreoviridin triggered PERK-mediated eIF2α phosphorylation, which in turn attenuated general protein synthesis and led to cell cycle arrest in the G0/G1 phase. We further showed that the combination of citreoviridin and the 26S proteasome inhibitor bortezomib could improve the anticancer activity by enhancing ER stress, by ameliorating citreoviridin-caused cyclin D3 compensation, and by contributing to CDK1 deactivation and PCNA downregulation. More interestingly, the combined treatment triggered lethality through unusual non-apoptotic caspase- and autophagy-independent cell death with a cytoplasmic vacuolization phenotype. The results imply that by boosting ER stress, the combination of ATP synthase inhibitor citreoviridin and 26S proteasome inhibitor bortezomib could potentially be an effective therapeutic strategy against breast cancer.

Background: Long non-coding RNAs (lncRNAs) have been the target of considerable attention for their roles in many biological processes. Only a small portion of lncRNAs are functionally characterized, and several approaches have been proposed for investigating the roles of these molecules, including how polymorphisms in lncRNA genomic sites may interfere with their function. Allele frequency variation in single nucleotide polymorphisms (SNPs), for example, has been associated with several diseases, including breast cancer (BC), the most common type of cancer in women., Methods: In the present study, we performed a systematic review of lncRNA SNPs associated with BC and a meta-analysis of some lncRNA SNPs. We found 31 SNPs mapped in 12 lncRNAs associated with BC in 28 case-control studies., Results: Our meta-analysis showed an insignificant difference between the SNPs rs217727, rs3741219, rs2107425 and rs2839698 on H19, as well as rs920778, rs1899663, rs12826786 and rs4759314 on HOTAIR, and BC susceptibility., Conclusions: The present analysis recognized the importance of extensive association studies, including different populations, and further evaluation of potential functional effects caused by lncRNA SNPs. Nevertheless, genetic variants such as SNPs in lncRNAs may play many other essential roles, although this field is still under explored., (© 2020 John Wiley & Sons, Ltd.)

Long noncoding RNAs (lncRNA) play pivotal roles in every level of gene and genome regulation. MCM3AP-AS1 is a lncRNA that has an oncogenic role in several kinds of cancers. Aberrant expression of MCM3AP-AS1 has been reported to be involved in the progression of diverse malignancies, including colorectal, cervical, prostate, lymphoma, lung, ovary, liver, bone, and breast cancers. It is generally believed that MCM3AP-AS1 expression is associated with cancer cell growth, proliferation, angiogenesis, and metastasis. MCM3AP-AS1 by targeting various signaling pathways and microRNAs (miRNAs) presents an important role in cancer pathogenesis. MCM3AP-AS1 as a competitive endogenous RNA has the ability to sponge miRNA, inhibit their expressions, and bind to different target mRNAs related to cancer development. Therefore, MCM3AP-AS1 by targeting several signaling pathways, including the FOX family, Wnt, EGF, and VEGF can be a potent target for cancer prediction and diagnosis. In this review, we will summarize the role of MCM3AP-AS1 in various human cancers., (© 2022. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Background: Breast phyllodes tumours (PTs) are graded as benign, borderline, or malignant by analysis of multiple histological features. PT grading is often inconsistent, likely due to variation in the weighting of grading criteria by pathologists., Design: The hierarchy of use of diagnostic criteria was identified using a 20-question survey., Results: In all, 213 pathologists from 29 countries responded. 54% reported 10-50 PT cases per year. Criteria considered key to PT diagnosis were: increased stromal cellularity (84.3%), stromal overgrowth (76.6%), increased stromal mitoses (67.8%), stromal atypia (61.5%), stromal fronding (59.0%), periductal stromal condensation (58.0%), irregular tumour borders (46.3%), and/or lesional heterogeneity (33.7%). The importance of grading parameters were: mitotic activity (55.5%), stromal overgrowth (54.0%), stromal atypia (51.9%), increased stromal cellularity (41.7%), and nature of the tumour border (38.9%). 49% would diagnose malignant PT without a full array of adverse features. 89% used the term "cellular fibroepithelial lesion (FEL)" for difficult cases; 45% would diagnose an FEL with stromal fronding (but lacking other PT features) as fibroadenoma (FA), 35% FEL, and 17% PT. 59% deemed clinico-radiological findings diagnostically significant; 68% considered age (≥40 years) important in determining if an FEL was a FA or PT. In FELs from young patients, increased stromal cellularity (83%), fronding (52%), and mitoses (41%) were more common. 34% regarded differentiating cellular FA from PT as a specific challenge; 54% had issues assigning a borderline PT grade., Conclusion: Criteria for grading PT lie on a spectrum, leading to interpretive variability. The survey highlights the criteria most used by pathologists, which do not completely align with WHO recommendations., (© 2022 John Wiley & Sons Ltd.)

Most breast cancers expressing the estrogen receptor α (ERα) are treated successfully with the receptor antagonist tamoxifen (TAM), but many of these tumors recur. Elevated expression of the homeodomain transcription factor HOXB13 correlates with TAM-resistance in ERα-positive (ER+) breast cancer, but little is known regarding the underlying mechanism. Our comprehensive evaluation of HOX gene expression using tiling microarrays, with validation, showed that distant metastases from TAM-resistant patients also displayed high HOXB13 expression, suggesting a role for HOXB13 in tumor dissemination and survival. Here we show that HOXB13 confers TAM resistance by directly downregulating ERα transcription and protein expression. HOXB13 elevation promoted cell proliferation in vitro and growth of tumor xenografts in vivo. Mechanistic investigations showed that HOXB13 transcriptionally upregulated interleukin (IL)-6, activating the mTOR pathway via STAT3 phosphorylation to promote cell proliferation and fibroblast recruitment. Accordingly, mTOR inhibition suppressed fibroblast recruitment and proliferation of HOXB13-expressing ER+ breast cancer cells and tumor xenografts, alone or in combination with TAM. Taken together, our results establish a function for HOXB13 in TAM resistance through direct suppression of ERα and they identify the IL-6 pathways as mediator of disease progression and recurrence., (©2013 AACR.)

Background: Molecular characterization of tumors has been critical for identifying important genes in cancer biology and for improving tumor classification and diagnosis. Long non-coding RNAs, as a new, relatively unstudied class of transcripts, provide a rich opportunity to identify both functional drivers and cancer-type-specific biomarkers. However, despite the potential importance of long non-coding RNAs to the cancer field, no comprehensive survey of long non-coding RNA expression across various cancers has been reported., Results: We performed a sequencing-based transcriptional survey of both known long non-coding RNAs and novel intergenic transcripts across a panel of 64 archival tumor samples comprising 17 diagnostic subtypes of adenocarcinomas, squamous cell carcinomas and sarcomas. We identified hundreds of transcripts from among the known 1,065 long non-coding RNAs surveyed that showed variability in transcript levels between the tumor types and are therefore potential biomarker candidates. We discovered 1,071 novel intergenic transcribed regions and demonstrate that these show similar patterns of variability between tumor types. We found that many of these differentially expressed cancer transcripts are also expressed in normal tissues. One such novel transcript specifically expressed in breast tissue was further evaluated using RNA in situ hybridization on a panel of breast tumors. It was shown to correlate with low tumor grade and estrogen receptor expression, thereby representing a potentially important new breast cancer biomarker., Conclusions: This study provides the first large survey of long non-coding RNA expression within a panel of solid cancers and also identifies a number of novel transcribed regions differentially expressed across distinct cancer types that represent candidate biomarkers for future research.

Unlabelled: The transcription factor ZNF217 is a candidate oncogene in the amplicon on chromosome 20q13 that occurs in 20% to 30% of primary human breast cancers and that correlates with poor prognosis. We show that Znf217 overexpression drives aberrant differentiation and signaling events, promotes increased self-renewal capacity, mesenchymal marker expression, motility, and metastasis, and represses an adult tissue stem cell gene signature downregulated in cancers. By in silico screening, we identified candidate therapeutics that at low concentrations inhibit growth of cancer cells expressing high ZNF217. We show that the nucleoside analogue triciribine inhibits ZNF217-induced tumor growth and chemotherapy resistance and inhibits signaling events [e.g., phospho-AKT, phospho-mitogen-activated protein kinase (MAPK)] in vivo. Our data suggest that ZNF217 is a biomarker of poor prognosis and a therapeutic target in patients with breast cancer and that triciribine may be part of a personalized treatment strategy in patients overexpressing ZNF217. Because ZNF217 is amplified in numerous cancers, these results have implications for other cancers., Significance: This study finds that ZNF217 is a poor prognostic indicator and therapeutic target in patients with breast cancer and may be a strong biomarker of triciribine treatment efficacy in patients. Because previous clinical trials for triciribine did not include biomarkers of treatment efficacy, this study provides a rationale for revisiting triciribine in the clinical setting as a therapy for patients with breast cancer who overexpress ZNF217.

Objective: To better understand the severity and impact of pain in women who are breast cancer survivors., Design: Cross-sectional survey., Setting: Cancer wellness clinic., Patients: Two hundred fifty-three women with a history of early-stage breast cancer who had completed therapy and were without evidence of disease. Interventions. None., Outcome Measures: A survey that included questions about cancer history, pain, sleep problems, and physical and psychological functioning., Results: About half of the participants (117 or 46%) reported some pain, although most rated its intensity as mild. Both average and worst pain ratings showed significant associations with physical functioning (rs, -0.48 and -0.43, respectively), severity of sleep problems (rs, 0.31 and 0.30), and psychological functioning (rs, -0.27 and -0.24). Age (with younger participants slightly more likely to report pain) and history of antiestrogen therapy showed nonsignificant trends to predict the presence of pain., Conclusions: The study findings provide new and important knowledge regarding the severity and impact of pain in female breast cancer survivors. The results indicate that clinicians should assess pain regularly in breast cancer survivors and treat this pain when indicated. The findings also support the need for research to determine whether improved pain management would result in improved quality of life for women with a history of breast cancer.

Emerging evidence shows that the lncRNA THOR is deeply involved in the development of various cancers. However, the effects and underlying molecular mechanisms of THOR in breast cancer (BRCA) initiation and progression have not been fully elucidated. Here we show that THOR is critical for BRCA tumorigenesis by interacting with hnRNPD to regulate downstream signaling pathways. THOR expression was significantly higher in BRCA tissues than in normal tissues, and THOR upregulation was associated with a poor prognosis in BRCA patients. Functionally, THOR knockdown impaired cell proliferation, migration and invasion in BRCA cells in vitro and inhibited tumorigenesis and metastasis in a tumor xenograft model and THOR-deficient MMTV-PyMT model in vivo. Mechanistically, THOR bound to the hnRNPD protein and increased hnRNPD protein levels by maintaining hnRNPD protein stability through inhibition of the proteasome-dependent degradation pathway. The increased hnRNPD protein levels led to stabilization of its target mRNAs, including pyruvate dehydrogenase kinase 1 (PDK1), further activating downstream PI3K-AKT and MAPK signaling pathways to regulate BRCA cell proliferation and metastasis. Together, our findings indicate that THOR is a promising prognostic predictor for BRCA patients and that the THOR-hnRNPD-PDK1-MAPK/PI3K-AKT axis might be a potential therapeutic target for BRCA treatment., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Invasive breast carcinomas are routinely tested for HER2 using immunohistochemistry (IHC), with reflex in situ hybridization (ISH) for those scored as equivocal (2+). ISH testing is expensive, time-consuming, and not universally available. In this study, we trained a deep learning algorithm to directly predict HER2 gene amplification status from HER2 2+ IHC slides. Data included 115 consecutive cases of invasive breast carcinoma scored as 2+ by IHC that had follow-up HER2 ISH testing. An external validation data set was created from 36 HER2 IHC slides prepared at an outside institution. All internal IHC slides were digitized and divided into training (80%), and test (20%) sets with 5-fold cross-validation. Small patches (256×256 pixels) were randomly extracted and used to train convolutional neural networks with EfficientNet B0 architecture using a transfer learning approach. Predictions for slides in the test set were made on individual patches, and these predictions were aggregated to generate an overall prediction for each slide. This resulted in a receiver operating characteristic area under the curve of 0.83 with an overall accuracy of 79% (sensitivity=0.70, specificity=0.82). Analysis of external validation slides resulted in a receiver operating characteristic area under the curve of 0.79 with an overall accuracy of 81% (sensitivity=0.50, specificity=0.82). Although the sensitivity and specificity are not high enough to negate the need for reflexive ISH testing entirely, this approach may be useful for triaging cases more likely to be HER2 positive and initiating treatment planning in centers where HER2 ISH testing is not readily available., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: It is unclear which psychological factors (stressors, emotional correlates, and psychophysiological markers) induce cancer risk. This currently limits the potential for prevention strategies., Purpose: The aim of this review is to bring forth evidence of stress as a determinant of cancer risk from a public health perspective, written for a broad public of practitioners and scientists., Methods: Based on a semisystematic literature search, the impact of different aspects/types of stress and the potential physiological and behavioral pathways are summarized, while highlighting further research, public health and clinical implications., Results: Between 2007 and 2020, 65 case-control or cohort studies have been identified. Apart from overall cancer ( N = 24), 12 cancer types have been associated with psychological stress with most for breast ( N = 21), colorectal ( N = 11) and lung/prostate/pancreas cancer ( N = 8 each). Although the evidence regarding the mechanisms is still scarce, cancer development in relation to stress might be due to interacting and combined effects of different stress(or) types, but such interaction has not really been tested yet. The path from stress towards cancer incidence consists of a biological pathway with endocrinology and immunology as well as stress-induced behavioral pathways, including smoking, alcoholism, sleep disruption, an unhealthy diet, and low physical activity together with the related phenomenon of obesity., Conclusion: Not only the stress but also the stress-induced lifestyle should be targeted for cancer prevention and treatment. Future research should include a more diverse spectrum of cancer types (not only hormonal related like breast cancer) and of stress measures while also considering behavioral covariates., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)