Tumor suppressive function of Matrin 3 in the basal-like breast cancer

BACKGROUND: Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. METHODS: We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. RESULTS: MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. CONCLUSIONS: Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.

Overexpression of histone deacetylase 11 suppresses basal-like breast cancer cell invasion and metastasis / 南方医科大学学报

OBJECTIVE@#Histone deacetylase 11 (HDAC11) is a class Ⅳ member of histone deacetylase family, and its role in regulating cancer cell invasion and metastasis remains unclear. We aimed to investigate the role of HDAC11 in regulating the biological behaviors of basal-like breast cancer (BLBC) cells.@*METHODS@#We analyzed the expression of HDAC11 based on Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA). The effects of HDAC11 on the cell invasion and metastasis were examined using Transwell assay and in a mouse model. The interaction between HDAC11 and Twist was detected with immunoprecipitation. We identified 2 as a target gene of Twist using promoter luciferase assay and chromatin immunoprecipitation assay.@*RESULTS@#HDAC11 was lowly expressed in BLBC cells. HDAC11 overexpression suppressed BLBC cell invasion and their metastasis in nude mice. Mechanistically, HDAC11 directly interacted with Twist protein, antagonized its pro-invasive function and repressed Twist-induced 2 gene transcription.@*CONCLUSIONS@#Our data suggest that HDAC11 acts as a negative modulator of invasion and metastasis of BLBC cells.

Tumour cell membrane laminin expression is associated with basal-like phenotype and poor survival in Nigerian breast cancer

Introduction: Laminin is a glycoprotein with diverse functions in carcinogenesis including cell proliferation, invasion, metastases and epithelial-mesenchymal transition (EMT). In breast cancer (BC) laminin expression is speculated to be associated with unfavourable clinicopathological and molecular characteristics. We hypothesize that laminin expression would contributed to the aggressive nature of basal like and triple negative BC phenotype observed in Black women. Methods: The expression of laminin was determined in a well-characterised Nigerian cohort of 255 BC using tissue microarray and immunohistochemistry. Laminin expression was compared with clinical, pathological and survival characteristics. Results: Laminin was expressed in 146 (57.3%) cases and significantly correlated with younger age at diagnosis (p=0.005), premenopausal status (p=0.003), expression of EGFR (p=0.002), ID4 and MTA1, basal cytokeratin 5/6, p53, and triple negative tumours (all p<0.001). In addition, there was an inverse association of laminin expression with E-cadherin (p=0.03), ER and PgR (all p<0.001) and a trend with BRCA1 (p=0.05). Univariate survival analysis showed tumours positive for laminin had significantly poorer breast cancer specific survival (BCSS, p=0.009) and disease free interval (p=0.03), but not associated in Cox multivariate analysis. Conclusion: This study demonstrates that laminin expression may have important roles in the aggressive nature observed in the basal-like and triple negative molecular subtype of Nigerian BC women.

Prognostic Significance of Basal Markers in Triple-negative Breast Cancers / 한국유방암학회지

PURPOSE: We have investigated the prognostic significance of the expression of basal markers for triple-negative (estrogen receptor-negative, progesterone receptor-negative and human epidermal growth factor receptor-2-negative) breast cancers (TNBCs). METHODS: An immunohistochemical study was performed on tissue microarrays constructed with 643 invasive breast carcinoma samples. We subclassified the TNBCs into basal phenotype (BP) and non-BP groups by the use of four different criteria according to the immunprofiles for cytokeratin5/6 (CK5/6), epidermal growth factor receptor (EGFR), vimentin, c-Kit, p63 and P-cadherin. The criteria consisted of criterion 1: CK5/6+ only, criterion 2: CK5/6+ and/or EGFR+, criterion 3: CK5/6+ and/or EGFR+ and/or vimentin+ and criterion 4: one or more marker(s) positive among the six basal markers. Each of these criteria, as well as the status of each individual marker, was evaluated to estimate prognosis for TNBC patients. RESULTS: Of the breast carcinomas, 165 cases (25.7%) were TNBCs. As compared with the non-TNBCs, TNBCs were associated with a larger tumor size (p=0.001), higher histological grade (p<0.001) and shorter overall survival (OS) (p=0.002) and disease-free survival (DFS) (p=0.05). Lymph node status, tumor size and expression of EGFR or c-Kit were independent prognostic factors for patients with TNBC. As compared with the non-BP, BP as defined by criterion 2 was an independent poor prognostic factor for OS and DFS among patients with a lymph node metastasis (p=0.044 and p=0.01) and among patients who received anthracycline-based adjuvant chemotherapy (p=0.009 and p=0.01, respectively). CONCLUSION: Patients with TNBCs showed a poorer prognosis as compared to patients with non-TNBCs. Selected group of the basal-like breast cancers (BLBCs) defined by the immunohistochemical profiles of basal markers showed survival differences from non-BLBCs in subgroups of TNBCs with a homogeneous clinical finding.

Progress in the study of triple negative breast cancer / 医学研究生学报

Triple-negative breast cancer (TNBC) is a subgroup of breast cancers defined by a lack of the expressions of estrogen,progesterone and HER2 receptors,with more aggressive biological and clinicopathological characteristics and a close relationship with basal-like and breast cancer susceptibility gene-1 (BRCA1)-related breast cancers.TNBC is insensitive to most available hormonal or standard therapeutic agents,associated with increased risk for distant metastases and with poorer prognosis than other types of breast cancer.A deeper insight into the biology of TNBC may lead to improved therapies and better clinical outcomes of the disease.