BackgroundTriple-negative breast cancer (TNBC) is a highly heterogeneous group of cancers, and molecular subtyping is necessary to better identify molecular-based therapies. While some classifiers have been established, no one has integrated the expression profiles of long noncoding RNAs (lncRNAs) into such subtyping criterions. Considering the emerging important role of lncRNAs in cellular processes, a novel classification integrating transcriptome profiles of both messenger RNA (mRNA) and lncRNA would help us better understand the heterogeneity of TNBC.MethodsUsing human transcriptome microarrays, we analyzed the transcriptome profiles of 165 TNBC samples. We used k-means clustering and empirical cumulative distribution function to determine optimal number of TNBC subtypes. Gene Ontology (GO) and pathway analyses were applied to determine the main function of the subtype-specific genes and pathways. We conducted co-expression network analyses to identify interactions between mRNAs and lncRNAs.ResultsAll of the 165 TNBC tumors were classified into four distinct clusters, including an immunomodulatory subtype (IM), a luminal androgen receptor subtype (LAR), a mesenchymal-like subtype (MES) and a basal-like and immune suppressed (BLIS) subtype. The IM subtype had high expressions of immune cell signaling and cytokine signaling genes. The LAR subtype was characterized by androgen receptor signaling. The MES subtype was enriched with growth factor signaling pathways. The BLIS subtype was characterized by down-regulation of immune response genes, activation of cell cycle, and DNA repair. Patients in this subtype experienced worse recurrence-free survival than others (log rank test, P = 0.045). Subtype-specific lncRNAs were identified, and their possible biological functions were predicted using co-expression network analyses.ConclusionsWe developed a novel TNBC classification system integrating the expression profiles of both mRNAs and lncRNAs and determined subtype-specific lncRNAs that are potential biomarkers and targets. If further validated in a larger population, our novel classification system could facilitate patient counseling and individualize treatment of TNBC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0690-8) contains supplementary material, which is available to authorized users.
Introduction The molecular mechanisms involved in breast cancer metastasis still remain unclear to date. In our previous study, differential expression of peroxiredoxin 6 was found between the highly metastatic MDA-MB-435HM cells and their parental counterparts, MDA-MB-435 cells. In this study, we investigated the effects of peroxiredoxin 6 on the proliferation and metastatic potential of human breast cancer cells and their potential mechanism.
To better understand the molecular mechanisms underlying breast cancer metastasis and search for potential markers for metastatic progression, we have developed a highly metastatic variant of human MDA-MB-435 breast cancer cell line through in vivo stepwise selection of pulmonary metastatic cells caused by parental MDA-MB-435 cells in the athymic mice. Comparative proteomic analysis using 2-DE and LC-IT-MS revealed that 102 protein spots were reproducibly altered more than three-fold between the selected variant and its parental counterpart. Eleven differentially expressed protein spots were identified with high confidence using SEQUEST with uninterpreted tandem mass raw data. Cathepsin D precursor, peroxiredoxin 6 (PDX6), heat shock protein 27 (HSP27), HSP60, tropomyosin 1 (TPM1), TPM2, TPM3, TPM4, 14-3-3 protein epsilon, and tumor protein D54 were up-regulated in the highly metastatic variant, whereas alpha B-crystalline (CRAB) was only detected in its parental counterpart. Differential expression was confirmed for four proteins including PDX6, CRAB, TPM4, and HSP60 by real-time quantitative PCR and Western blotting analysis in our model. Immunohistochemical analysis in 80 breast cancer donors demonstrated a significant association of TPM4 (p = 0.002), HSP60 (p = 0.001), PDX6 (p = 0.002) but not CRAB (p = 0.113) staining with the presence of lymph node metastasis. In addition, TPM4 staining was also associated with clinical stage (p = 0.000), but no significant association was found between TPM4, PDX6, CRAB, and HSP60 expression and tumor size, hormone receptor, and HER-2 status (p > 0.05). The functional implication of these identified proteins was also discussed. These proteomic data are valuable and informative for understanding breast cancer metastasis and searching for potential markers for metastatic progression.
To have an overview of the role of BRCA1 and BRCA2 genes among Chinese high-risk breast cancer patients, we analyzed 489 such high-risk breast cancer patients from four breast disease clinical centers in China, by using PCR-DHPLC or SSCP-DNA sequencing analysis. Allelotype analysis was done at five short tandem repeat (STR) markers in or adjacent to BRCA1 on the recurrent mutation carriers. For those analyzed both genes, 8.7% of early-onset breast cancer cases and 12.9% of familial breast cancer cases had a BRCA1 or BRCA2 mutation, as compared with the 26.1% of cases with both early-onset breast cancer and affected relatives. For those reporting malignancy family history other than breast/ovarian cancer, the prevalence of BRCA1/2 mutation is about 20.5%, and it was significantly higher than the patients only with family history of breast/ovarian cancer (P = 0.02). The family history of ovarian cancer (26.7% vs. 11.9%) and stomach cancer (23.8% vs. 11.8%) doubled the incidence of BRCA1/2, but the difference did not reach the statistical significance. Two recurrent mutations in BRCA1, 1100delAT and 5589del8, were identified. The recurrent mutations account for 34.8% BRCA1 mutations in our series. Similar allelotypes were detected in most STR status for those harboring the same mutations. The BRCA1 associated tumors were more likely to exhibit a high tumor grade, negative C-erbB-2/neu status and triple negative (ER, PgR and C-erbB-2/neu negative) status (P < 0.05). We recommended the BRCA1 and BRCA2 genetic analysis could be done for high-risk breast cancer patient in Chinese population, especially for those with both early-onset breast cancer and affected relatives. There may be some degree of shared ancestry for the two recurrent BRCA1 mutations in Chinese.
Twenty-five to thirty percent of patients with node-negative breast cancer are expected to relapse following surgery, therefore great efforts have been made to identify new prognostic markers that could be useful in defining patients for additional therapy. The expression of MMP-2 and MMP-9 has been associated with high potential of metastasis in several human carcinomas including breast cancer. In the present study we examined the prognostic value of immunoreactive MMP-2/MMP-9 protein in 270 consecutive lymph node negative cases who received radical mastectomy or modified radical mastectomy. Among the patients, 211 cases received adjuvant endocrine therapy and/or adjuvant chemotherapy. Using immunohistochemical assay, we found that 56.7% of the resected tumors were positive for MMP-2 whereas 59.6% of the samples were positive for MMP-9. Chi2 test demonstrated a significant direct association between MMP-2 and MMP-9 (p < 0.001); positive immunostaining of MMP-2 was significantly related to higher tumor grade (p < 0.001) and larger tumor size (p = 0.012); positive immunostaining of MMP-9 was significantly related to higher tumor grade (p = 0.002). In univariate analysis, using Cox-proportional hazard model we found MMP-2, MMP-9 and the co-expression of MMPs (MMP2/MMP9) were significantly associated with patients' relapse free survival (p = 0.016, 0.015 and 0.013 respectively) but not overall survival (p = 0.122, 0.320 and 0.091 respectively). Log-rank test also showed that MMP-2, MMP-9 or the co-expression of MMP2/MMP9 was unfavorable prognostic factor for relapse free survival but not overall survival. In subgroup analysis, we found MMPs were more prognostic for patients with no adjuvant treatment than for patients with adjuvant therapy. In multivariate analysis, using Cox-proportional hazard model we found co-expression of MMPs, larger tumor size and higher tumor grade were unfavorable for relapse free survival (p = 0.038, 0.007 and 0.015 for each). We concluded that MMP-2 and MMP-2 are unfavorable prognostic factors in breast cancer patients. They might be potential predictive factor for adjuvant systemic therapy. The co-expression of MMP-2 and MMP-9 has significantly prognostic value in node-negative patients.
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