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Although targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer has significantly prolonged survival time and improved patients' quality of life, drug resistance has gradually emerged. This study explored the mechanisms underlying the effect of the motor neuron and pancreatic homeobox 1 (MNX1) genes on drug sensitivity in HER2-positive breast cancer. From July 2017 to 2018, core needle biopsies of HER2-positive breast cancer were collected from patients who received paclitaxel, carboplatin, and trastuzumab neoadjuvant therapy at our center. Based on treatment efficacy, 81 patients were divided into pathological complete response (pCR) and non-pCR groups. High-throughput RNA sequencing results were analyzed along with the GSE181574 dataset. MNX1 was significantly upregulated in the pCR group compared with the non-pCR group in both sequencing datasets, suggesting that MNX1 might be correlated with drug sensitivity in HER2-positive breast cancer. Meanwhile, tissue array results revealed that high MNX1 expression corresponded to a good prognosis. In vitro functional tests showed that upregulation of MNX1 significantly increased the sensitivity of HER2-positive breast cancer cells to lapatinib and pyrotinib. In conclusion, MNX1 may serve as a prognostic marker for patients with HER2-positive breast cancer, and its expression may facilitate clinical screening of patients sensitive to anti-HER2-targeted therapy. [ABSTRACT FROM AUTHOR]

Purpose: The function of stanniocalcin‐1 (STC‐1) in the oncogenesis and progression of tumors has been extensively studied. The purpose of this study was to investigate the relationship between secreted STC‐1 and prognosis in patients with breast cancer (BC) and to determine whether STC‐1 could be a key prognostic factor in BC. Methods: The STC‐1 level was measured by ELISA and clinical data from 1210 female patients with BC were used to develop and validate nomograms. We then verified the models through the plotting of ROC curves and calibration curves, calculating the C‐index, and performing decision curve analyses (DCA). Results: The level of STC‐1 in the peripheral plasma was significantly correlated with the T stage, N stage, clinical stage, grade, hormone receptors, HER‐2 status, and tumor subtype. Cox regression analyses revealed that estrogen receptor(ER) status, N stage, and STC‐1 level were risk factors for overall survival (OS), whereas T stage, N stage, and STC‐1 level were independent prognostic factors for distant disease‐free survival (DDFS) and disease‐free survival (DFS). Both the ROC curve and the C‐index confirmed the high resolution of these models, while the DCA identified the feasibility of their practical application. In addition, the calibration curves indicated good consistency between the predicted and actual survival rates. Conclusion: Nomograms were created based on STC‐1 levels for 3‐, 5‐, and 7‐year OS, DDFS, and DFS of patients with BC respectively. As a key prognostic factor for BC, peripheral blood STC‐1 level can be used clinically as a liquid biopsy indicator. [ABSTRACT FROM AUTHOR]

Background: Compared with older patients, young women with breast cancer (YWBCs) have a poorer prognosis and a higher risk of recurrence. Ages ≤35 years are independent risk factors for local recurrence of breast cancer. Surgery is the most important local treatment for YWBC, and there is still a lack of prospective studies comparing surgical options for recurrence and survival. We retrospectively compared the effects of surgical options on disease-free survival (DFS) and overall survival (OS) of YWBC at Fudan University Shanghai Cancer Center (FUSCC). Methods: YWBCs (age ≤35 years) who underwent surgery at FUSCC between 2008 and 2016 were retrospectively analyzed and divided into three groups according to surgical options: 1) breast-conserving surgery (BCS), 2) mastectomy alone (M), and 3) mastectomy with reconstruction (RECON). The DFS and OS outcome rates from the three surgical options were compared using the Kaplan–Meier method and Cox regression model. Propensity score matching (PSM) was also used to balance the baseline characteristics to eliminate selection bias. Results: A total of 1,520 YWBCs were enrolled with a median follow-up of 5.1 years, including 524 patients (34.5%) who underwent BCS, 676 patients (44.5%) who underwent M, and 320 patients (21.1%) who underwent RECON. The 5-year DFS rates were 96%, 87%, and 93%, respectively (P < 0.001); the 5-year OS rates were 98%, 94%, and 97%, respectively (P = 0.002). Multivariate Cox analysis showed that DFS and OS were significantly improved in patients undergoing BCS compared with those undergoing M, with hazard ratios (HR) of 0.448 (95% CI 0.276–0.728; P = 0.001) and 0.405 (95% CI 0.206–0.797, P = 0.009), respectively. After PSM, DFS and OS rates were significantly improved in patients undergoing BCS compared to patients undergoing M (DFS, P = 0.001; OS, P = 0.009); RECON was also improved compared to patients undergoing M in terms of DFS and OS, but the difference was not statistically significant (DFS, P = 0.164; OS, P = 0.130). Conclusions: The surgical options were independent factors affecting DFS and OS in YWBC, and the DFS and OS rates were significantly improved in the BCS group compared to those in the M group. BCS is preferred for early YWBC, and RECON is the best option for remodeling the body images of YWBC who do not have breast-conserving conditions. [ABSTRACT FROM AUTHOR]

Background: LncRNAs have been shown to play critical roles in regulating tumorigenesis and tumor progression. Using LncRNAs to predict prognosis and therapeutic response to cancer treatment has been caused for concern, but the predictive value of lncRNAs remains to be explored and underlying mechanisms have not been completely understood. Methods: The Linc01315 expression level was detected in 282 breast cancer tissues by using quantitative RT-PCR. The association between Linc01315 expression level and clinicopathological features of these breast cancer patients was further analyzed. Multiple regression analysis was used to evaluate Linc01315 predictive value of patients' prognosis. Results: Our study revealed that Linc01315 expression level was significantly correlated with vessel invasion (P = 0.028) and tumor subtype (P = 0.039). The Kaplan–Meier survival curves demonstrated that patients with lower Linc01315 expression level had significantly longer disease free survival (DFS) (P = 0.002) and overall survival (OS) (P =0.019). Multiple regression analysis showed that Linc01315 level could be an independent predictive factor for DFS (hazards ratio = 0.613, 95% confidence interval = 0.375-1.003; P = 0.049) and OS (hazards ratio = 0.439, 95% confidence interval = 0.228-0.845; P = 0.014). Further analysis showed that low Linc01315 level patients with endocrine therapy could benefit patients DFS (P =0.037) and OS (P =0.025). Conclusion: Our results demonstrate that Linc01315 expression level is significantly correlated with breast cancer patients' prognosis. Linc01315 may represent an independent prognostic marker and therapeutic target in breast cancer. [ABSTRACT FROM AUTHOR]

Abstract Background GADD45B is a member of the growth arrest DNA damage-inducible gene family associated with cell growth control, apoptosis, and DNA damage repair response. The aim of this study is to detect the role of GADD45B in colorectal carcinoma (CRC); the area not studied in depth to date. Methods The mRNA and protein levels of GADD45B were examined by Real-Time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) in CRC tissues and adjacent noncancerous tissues (ANCT). Over-expression plasmids and SiRNA were used to regulate GADD45B expression in CRC cell lines in vitro and flow cytometry and Western blotting were used to detect apoptotic changes. Results The mRNA and protein levels of GADD45B were significantly higher in CRC tissues than those in ANCT (PP Conclusion GADD45B, a tumor suppressor gene potentially through the p53-mediated apoptotic pathways, is paradoxically overexpressed in CRC and as such may play an unappreciated role in tumorigenesis. The exact mechanism of GADD45B inactivation and overexpression requires further investigation. GADD45B could be a potential therapeutic target for CRC treatment in future.

Background: The objective of this study was to determine an axillary pathologic complete response (pCR) and its influencing factors in patients with hormone receptor (HR)-positive breast cancer and cytologically proven axillary lymph node metastases. A prediction nomogram was established to provide information for the de-escalation of axillary management in these patients after neoadjuvant chemotherapy.Methods: The authors retrospectively enrolled all patients with HR-positive breast cancer in the neoadjuvant chemotherapy data set of Fudan University Shanghai Cancer Center. All data were prospectively collected. From 2007 to 2016, 533 consecutive patients were included. Multivariate logistic regression analysis was performed, after which a nomogram was constructed and validated.Results: An axillary pCR was achieved in 168 patients (31.5%), the which was much higher than the proportion of those who achieved a breast pCR (103 patients; 19.3%). Patients who had human epidermal growth factor receptor 2-positive disease (P = .004), a better primary tumor response (P = .001), earlier clinical stage (P = .045), and lower estrogen receptor expression (P < .001) were more likely to achieve a lymph node pCR. The nomogram indicated an area under the receiver operating characteristic curve (AUC) of 0.84 (95% CI, 0.78-0.89) in the training set. The validation set showed good discrimination with an AUC of 0.75 (95% CI, 0.69-0.81). The C-index was 0.834 and 0.756 in the training and validation cohort, respectively. The nomogram was well calibrated.Conclusions: The authors developed and validated a nomogram for predicting axillary pCR in patients with HR-positive disease accurately by using clinicopathologic factors available before surgery. The model will facilitate logical clinical decision making and clinical trial design. [ABSTRACT FROM AUTHOR]

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The genetic etiology of hereditary breast cancer has not been fully elucidated. Although germline mutations of high-penetrance genes such as BRCA1/2 are implicated in development of hereditary breast cancers, at least half of all breast cancer families are not linked to these genes. To identify a comprehensive spectrum of genetic factors for hereditary breast cancer in a Chinese population, we performed an analysis of germline mutations in 2,165 coding exons of 152 genes associated with hereditary cancer using next-generation sequencing (NGS) in 99 breast cancer patients from families of cancer patients regardless of cancer types. Forty-two deleterious germline mutations were identified in 21 genes of 34 patients, including 18 (18.2%) BRCA1 or BRCA2 mutations, 3 (3%) TP53 mutations, 5 (5.1%) DNA mismatch repair gene mutations, 1 (1%) CDH1 mutation, 6 (6.1%) Fanconi anemia pathway gene mutations, and 9 (9.1%) mutations in other genes. Of seven patients who carried mutations in more than one gene, 4 were BRCA1/2 mutation carriers, and their average onset age was much younger than patients with only BRCA1/2 mutations. Almost all identified high-penetrance gene mutations in those families fulfill the typical phenotypes of hereditary cancer syndromes listed in the National Comprehensive Cancer Network (NCCN) guidelines, except two TP53 and three mismatch repair gene mutations. Furthermore, functional studies of MSH3 germline mutations confirmed the association between MSH3 mutation and tumorigenesis, and segregation analysis suggested antagonism between BRCA1 and MSH3. We also identified a lot of low-penetrance gene mutations. Although the clinical significance of those newly identified low-penetrance gene mutations has not been fully appreciated yet, these new findings do provide valuable epidemiological information for the future studies. Together, these findings highlight the importance of genetic testing based on NCCN guidelines and a multi-gene analysis using NGS may be a supplement to traditional genetic counseling. [ABSTRACT FROM AUTHOR]

Abstract: Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and regulates transcription of target genes. In this study, we identified CDK11p58 as a novel protein involved in the regulation of VDR. CDK11p58, a member of the large family of p34cdc2-related kinases, is associated with cell cycle progression, tumorigenesis, and apoptotic signaling. Our study demonstrated that CDK11p58 interacted with VDR and repressed VDR-dependent transcriptional activation. Furthermore, overexpression of CDK11p58 decreased the stability of VDR through promoting its ubiquitin–proteasome-mediated degradation. Taken together, these results suggest that CDK11p58 is involved in the negative regulation of VDR. [Copyright &y& Elsevier]

Abstract: BCL2L12 has been found to be associated with favorable prognosis in breast cancer patients while correlated with tumorigenesis of glioblastoma and colon cancer. Here, we report that BCL2L12 and its transcript variant BCL2L12A are degraded through ubiquitin-proteasome system (UPS). Interestingly, the ubiquitinations and degradations of BCL2L12 and BCL2L12A are independent of the internal lysine residues but the first N-terminal residues. In addition, HSP70 was identified to interact with BCL2L12 and BCL2L12A and protected them from ubiquitinations and degradations in mammalian cells. In summary, HSP70 protects BCL2L12 and BCL2L12A from N-terminal ubiquitination-mediated proteasomal degradation. Structured summary: MINT-7026352, MINT-7026366: BCL2L12 (uniprotkb:Q9HB09-1) physically interacts (MI:0218) with Hsp70 (uniprotkb:P62988) by anti tag coimmunoprecipitation (MI:0007) MINT-7026290: BCL2L12 (uniprotkb:Q9HB09-1) physically interacts (MI:0218) with ubiquitin (uniprotkb:P62988) by pull down (MI:0096) MINT-7026326: Hsp70 (uniprotkb:P08107) physically interacts (MI:0218) with BCL2L12A (uniprotkb:Q9HB09-2) by anti bait coimmunoprecipitation (MI:0006) MINT-7026338: BCL2L12 (uniprotkb:Q9HB09-1) physically interacts (MI:0218) with Hsp70 (uniprotkb:P08107) by anti tag coimmunoprecipitation (MI:0007) MINT-7026304: BCL2L12A (uniprotkb:Q9HB09-2) physically interacts (MI:0218) with Hsp70 (uniprotkb:P08107) by anti tag coimmunoprecipitation (MI:0007) [Copyright &y& Elsevier]

Abstract: CDK11p58, a 58kDa protein of the PITSLRE kinase family, plays an important role in cell cycle progression, and is closely related to cell apoptosis. To gain further insight into the function of CDK11p58, we screened a human fetal liver cDNA library for its interacting proteins using the yeast two-hybrid system. Here we report that histone acetyltransferase (HAT) HBO1, a MYST family protein, interacts with CDK11p58 in vitro and in vivo. CDK11p58 and HBO1 colocalize in the cell nucleus. Recombinant CDK11p58 enhances the HAT activity of HBO1 significantly in vitro. Meanwhile, overexpression of CDK11p58 in mammalian cells leads to the enhanced HAT activity of HBO1 towards free histones. Thus, we conclude that CDK11p58 is a new interacting protein and a novel regulator of HBO1. Both of the proteins may be involved in the regulation of eukaryotic transcription. [Copyright &y& Elsevier]

Phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), which functions as a marker of endoplasmic reticulum stress, has been reported to be associated with patient prognosis in various cancers. However, little is known about the prognostic value of p-eIF2α in breast cancer, particularly in different breast cancer subtypes. An immunohistochemistry screen for p-eIF2α was performed using a tissue microarray containing 233 tumors and paired peritumoral tissues from female patients diagnosed with breast cancer. The staining results were scored semiquantitatively, and the p-eIF2α expression level in breast cancer and its potential prognostic value were investigated. In this retrospective cohort study, we found that p-eIF2α levels were significantly upregulated in breast cancer (P < 0.001). p-eIF2α level was negatively correlated with lymph node status (P = 0.039). Survival analysis by Kaplan-Meier estimation and Cox regression showed that p-eIF2α level was correlated with better disease free survival (P = 0.026) and served as an independent prognostic factor (P = 0.046) in patients with triple-negative breast cancer. Our study revealed that p-eIF2α was upregulated in breast cancer and represented a novel predictor of prognosis in patients with triple-negative subtype. [ABSTRACT FROM AUTHOR]

Current bio-medical imaging researches aim to detect brain micrometastasis in early stage for its increasing incidence and high mortality rates. Synchrotron phase-contrast imaging techniques, such as in-line phase-contrast (IPC) and grating-based phase-contrast (GPC) imaging, could provide a high spatial and density imaging study of biological specimens' 3D structures. In this study, we demonstrated the detection efficiencies of these two imaging tools on breast cancer micrometastasis in an ex vivo mouse brain. We found that both IPC and GPC can differentiate abnormal brain structures induced by micrometastasis from the surrounding normal tissues. We also found that GPC was more sensitive in detecting the small metastasis as compared to IPC. [ABSTRACT FROM AUTHOR]

Background: CDK11(p58), a Ser/Thr kinase that belongs to the cell division cycle 2-like 1 (CDC2L1) subfamily, is associated with cell cycle progression, tumorigenesis and apoptotic signaling. CDK11(p58) is also involved in the regulation of steroid receptors, such as androgen and estrogen receptors. We previously found that CDK11(p58) was abnormally expressed in prostate cancer. However, its role in breast cancer remains unclear.Methods: CDK11(p58) expression was evaluated by immunohistochemical staining in a tissue array. A Transwell assay was used to detect invasion and metastasis in breast cancer cells. The TaqMan® Metastasis Gene Expression Assay was used to search for potential downstream factors in the CDK11(p58) signaling pathway. qRT-PCR was used to evaluate mRNA levels, and the dual luciferase array was used to analyze promoter activity. Western blotting was used to detect the protein level.Results: CDK11(p58) expression was negatively correlated with node status (P = 0.012), relapse status (P = 0.002) and metastasis status (P = 0.023). Kaplan-Meier survival curves indicated that the disease-free survival (DFS) was significantly poor in breast cancer patients with low CDK11 expression. Interestingly, using the breast cancer cell lines ZR-75-30 and MDA-MB-231, we found that CDK11(p58) was capable of repressing the migration and invasion of ERα-positive breast cancer cells, but not ERα-negative breast cancer cells, in a kinase-dependent manner. Gene expression assays demonstrated that integrin β3 mRNA was dramatically repressed by CDK11(p58), and luciferase results confirmed that the integrin β3 promoter was inhibited by CDK11(p58) through ERα repression. The expression of integrin β3 was highly related to ERα signaling; ERα overexpression stimulated integrin β3 expression, whereas siRNA-mediated knockdown of ERα attenuated integrin β3 expression.Conclusions: These data indicate that CDK11(p58) is an anti-metastatic gene in ERα-positive breast cancer and that the regulation of integrin β3 by CDK11(p58) via the repression of ERα signaling may constitute part of a signaling pathway underlying breast cancer invasion. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) remains one of the most common cancers worldwide. We observed that MUC20 was significantly up-regulated in CRC patients with poor prognosis based on the microarray analysis. However, little is known about the role of MUC20 in CRC.Methods: Microarray experiments were performed on the Affymetrix U133 plus 2.0 GeneChip Array. The protein and mRNA levels of MUC20 were examined by immunohistochemistry (IHC) and Real-Time quantitative PCR (RT-qPCR) in CRC tissues and adjacent noncancerous tissues (ANCT). ShRNA and overexpression plasmids were used to regulate MUC20 expression in CRC cell lines in vitro; wound healing, Transwell migration assays, and Western blotting were used to detect migration and invasion changes.Results: MUC20 was one of the up-regulated genes in CRC patients with poor prognosis by microarray. Using IHC and RT-qPCR, we showed that MUC20 expression was significantly higher in CRC tissues than in ANCT (P < 0.05). We further showed that MUC20 overexpression was correlated with recurrence and poor outcome (P < 0.05). The Kaplan-Meier survival curves indicated that disease-free survival (DFS) and overall survival (OS) were significantly worse in CRC patients with MUC20 overexpression. The Cox multivariate analysis revealed that MUC20 overexpression and TNM stage were independent prognostic factors. Elevated expression of MUC20 in cells promoted migration and invasion, whereas ShRNA-mediated knockdown inhibited these processes. In addition, Western blotting demonstrated that MUC20-induced invasion was associated with MMP-2, MMP-3, and E-cadherin.Conclusions: Cumulatively, MUC20 may serve as an important predictor of recurrence and poor outcome for CRC patients. MUC20 overexpression could enhance migration and invasion abilities of CRC cells. Translation of its roles into clinical practice will need further investigation and additional test validation. [ABSTRACT FROM AUTHOR]

Abstract: The pathogenesis of microsatellite stable hereditary non-polyposis colorectal cancers (MSS HNPCC) is unclear. To identify genomic regions that might be involved in MSS HNPCC pathogenesis, we selected 20 pairs of MSS HNPCC for a genome-wide study using copy number variation targeted (CNV-targeted) CytoScan HD Array. A remarkably increased frequency of 20q gain (70%) and high levels of copy-neutral loss of heterozygosity (40%) were observed. The most frequent tumor-specific CNVs included amplifications (7p21.3-15.1, 8q13.3-24.3, 13q14.1-33.3 and 20q12-13.33) and deletions (8p11.23-23.1, 15q11.2-26.1, 17p13.1-13.3 and 18q11.2-21.33). In addition, 10 novel CNVs were discovered and led to identification of WDR16 and RAPGEF5 as candidate genes involved in tumorigenesis, displaying a robust correlation between expression and genomic alterations. Moreover, WDR16 and RAPGEF5 exhibited altered protein expression levels as assessed by immunohistochemistry (IHC) in 41 other independent samples. Finally, high consistencies (68–84%) were observed between CNVs by Array and quantitative PCR. These findings are important for further elucidating MSS HNPCC pathogenesis. [Copyright &y& Elsevier]