miRNA-135b Contributes to Triple Negative Breast Cancer Molecular Heterogeneity: Different Expression Profile in Basal-like Versus non-Basal-like Phenotypes

Abstract

The clinical and genetic heterogeneity of Triple Negative Breast Cancer (TNBC) and the lack of unambiguous molecular targets contribute to the inadequacy of current therapeutic options for these variants. MicroRNAs (miRNA) are a class of small highly conserved regulatory endogenous non-coding RNA, which can alter the expression of genes encoding proteins and may play a role in the dysregulation of cellular pathways. Our goal was to improve the knowledge of the molecular pathogenesis of TNBC subgroups analyzing the miRNA expression profile, and to identify new prognostic and predictive biomarkers.We conducted a human miRNome analysis by TaqMan Low Density Array comparing different TNBC subtypes, defined by immunohistochemical basal markers EGFR and CK5/6. RT-qPCR confirmed differential expression of microRNAs. To inspect the function of the selected targets we perform Gene Ontology and KEGG enrichment analysis.We identified a single miRNA signature given by miR-135b expression level, which was strictly related to TNBC with basal-like phenotype. miR-135b target analysis revealed a role in the TGF-beta, WNT and ERBB pathways. A significant positive correlation was identified between neoplastic proliferative index and miR-135b expression.These findings confirm the oncogenic roles of miR-135b in the pathogenesis of TNBC expressing basal markers. A potential negative prognostic role of miR-135b overexpression might be related to the positive correlation with high proliferative index. Our study implies potential clinical applications: miR-135b could be a potential therapeutic target in basal-like TNBCs.

Genome-wide DNA methylation and expression patterns of microRNAs in relation to breast cancer subtypes among American women of African and European ancestry

“…By contrast, we observed CpG promoter hypomethylation and upregulation of miR-135b in ER-versus ER + tumors. Consistent with these results, several studies have reported miR-135b was upregulated in ER-or triple negative breast cancers and its overexpression promotes breast cancer progression and metastasis through regulation of ERα, AR, and other genes such as LATS2, TGFβ, WNT, and HIF1AN (37)(38)(39)(40)(41). Taken together, con rmed in TCGA data, these consistent negative correlations between CpG methylation and miRNA expression support the notion that, at least in some cases, altered miRNA expression may occur through mechanisms involving loss or gain of promoter DNA methylation during early stages of carcinogenesis and contribute to the development of speci c subtypes of the disease.…”

Exploring specific prognostic biomarkers in triple-negative breast cancer

“…Previously, miR-135b-5p has been well documented as a tumor suppressor [33][34][35] or oncogene [36][37][38] in breast cancer, but less is known about the expression and function of miR-135b-3p. In case that both 5p and 3p strands are functional and not degraded, despite targeting different mRNAs, they might cooperate temporally and result in a synergistic effect.…”

Modulatory Role of microRNAs in Triple Negative Breast Cancer with Basal-Like Phenotype

“…MiR-135b overexpression was highly related to TNBC with BLP and played a role in the TGF-beta, WNT, and HER2 pathways, confirming its involvement in TNBC with BLP pathogenesis. The miR-135b overexpression had a negative prognostic role that might be linked to a positive correlation with elevated proliferative index: modification of miR-135b expression could represent a therapeutic target in basal-like TNBCs [74]. Furthermore, previous studies showed miR-135b overexpression in TNBC and its downregulation in luminal tumors [18,[75][76][77].…”

“…Cell proliferation, AR status, and age [18,[74][75][76]139] miR-421 PIEZO2, PDCD4 Cell proliferation [156] miR-454-3p PIEZO2, AKT Cell proliferation, migration, invasion, and apoptosis [156] miR-301a-3p, PTEN, ER, PIEZO2…”