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

Abstract

Development of new research, classification, and therapeutic options are urgently required due to the fact that TNBC is a heterogeneous malignancy. The expression of high molecular weight cytokeratins identifies a biologically and clinically distinct subgroup of TNBCs with a basal-like phenotype, representing about 75% of TNBCs, while the remaining 25% includes all other intrinsic subtypes. The triple negative phenotype in basal-like breast cancer (BLBC) makes it unresponsive to endocrine therapy, i.e., tamoxifen, aromatase inhibitors, and/or anti-HER2-targeted therapies; for this reason, only chemotherapy can be considered an approach available for systemic treatment even if it shows poor prognosis. Therefore, treatment for these subgroups of patients is a strong challenge for oncologists due to disease heterogeneity and the absence of unambiguous molecular targets. Dysregulation of the cellular miRNAome has been related to huge cellular process deregulations underlying human malignancy. Consequently, epigenetics is a field of great promise in cancer research. Increasing evidence suggests that specific miRNA clusters/signatures might be of clinical utility in TNBCs with basal-like phenotype. The epigenetic mechanisms behind tumorigenesis enable progress in the treatment, diagnosis, and prevention of cancer. This review intends to summarize the epigenetic findings related to miRNAome in TNBCs with basal-like phenotype.

Keywords: TNBC molecular classification; basal-like breast cancer; breast cancer; epigenetic modulation; intrinsic molecular subtypes; microRNA; triple negative breast cancer.

Figure 1

Molecular and phenotypic heterogeneity of Triple Negative breast cancer (TNBC): (A) pie chart showing frequencies and molecular TNBC type-6 classification (according to Lehmann et al. 2011) [13]; (B) pie chart displaying frequencies and molecular TNBC type-4 classification (according to Lehmann et al. 2011) [41]; (C) TNBC assigned to intrinsic molecular breast cancer (BC) subtypes (according to Lehmann et al. 2011) [13]; (D) pie chart showing molecular subclassification and frequencies of basal-like phenotype (BLP) in TNBC (according to Prat et al. 2013) [44]; (E) pie chart displaying molecular subclassification and frequencies of TNP in BLBC (according to Prat et al. 2013) [44]; (F) pie chart showing the fuzzy clustering of TNBC (according to Jezequel et al.) [45]; (G) pie chart displaying the probabilistic graphical model of TNBC (according to Prado-Vazquez et al.) [42]; (H) pie chart showing the overlapping between the probabilistic graphical model of TNBC and the immune activity negative group (according to Prado-Vazquez et al.) [42]; and (I) pie chart displaying the overlapping between the probabilistic graphical model of TNBC and the immune activity-positive group (according to Prado-Vazquez et al.) [42]. BL, basal-like; BL1, basal-like 1; BL2, basal-like 2; CLDN, Claudin; HER2, human epidermal growth factor receptor 2; HR−, hormone receptor negative; HR+, hormone receptor positive; IM, immunomodulatory; LAR, luminal AR; M, mesenchymal; MSL, mesenchymal stem-like; NBC, non-basal-like; NL, normal-like; and UNS, unstable.

Figure 2

Current advances in systematic treatment for patients affected by different TNBC subtypes [46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66].

Figure 3

miRNAs/mRNA complex network in TNBC with basal-like phenotype and potential sites of therapeutic interventions.