Breast Cancer Subtype-Specific miRNAs: Networks, Impacts, and the Potential for Intervention

Abstract

The regulatory and functional roles of non-coding RNAs are increasingly demonstrated as critical in cancer. Among non-coding RNAs, microRNAs (miRNAs) are the most well-studied with direct regulation of biological signals through post-transcriptional repression of mRNAs. Like the transcriptome, which varies between tissue type and disease condition, the miRNA landscape is also similarly altered and shows disease-specific changes. The importance of individual tumor-promoting or suppressing miRNAs is well documented in breast cancer; however, the implications of miRNA networks is less defined. Some evidence suggests that breast cancer subtype-specific cellular effects are influenced by distinct miRNAs and a comprehensive network of subtype-specific miRNAs and mRNAs would allow us to better understand breast cancer signaling. In this review, we discuss the altered miRNA landscape in the context of breast cancer and propose that breast cancer subtypes have distinct miRNA dysregulation. Further, given that miRNAs can be used as diagnostic and/or prognostic biomarkers, their impact as novel targets for subtype-specific therapy is also possible and suggest important implications for subtype-specific miRNAs.

Keywords: breast cancer; estrogen receptor (ER); human epidermal growth factor receptor 2 (HER2); microRNA (miRNA); progesterone receptor (PR); prognosis; subtype specificity; triple negative breast cancer (TNBC).

Figure 1

Examples of significant microRNAs (miRNAs) associated with specific breast cancer subtypes and their effects on cell phenotypes. In estrogen receptor positive/progesterone receptor positive (ER+/PR+) breast cancers (blue box), we note the role of miR-100 and miR-30 families and the distinction between the luminal A and luminal B molecular subtypes. In human epidermal growth factor receptor 2 positive (HER2+) breast cancers (yellow box), we have noted miR-4728-3p, which is present in the intronic region of HER2 and is co-expressed with HER2. The miRNA is involved in feedback regulation of HER2 and oncogenic miR-21-5p. This facilitates several oncogenic processes in later stage tumors. In triple negative breast cancers (TNBCs) (purple box), we have noted the cMYC oncogene driven miR-17~92 cluster, which is overexpressed in TNBCs, specifically the BL1 molecular subtype. The miRNA cluster promotes proliferation through its direct targets, which include phosphate and tensin homolog (PTEN) and inositol polyphosphate-4-phosphatase type II B (INPP4B) and are inhibitors of the proliferation mediator AKT. The migratory phenotype of TNBC cell lines that fall within the mesenchymal stem like (MSL) and mesenchymal (M) molecular subtypes is facilitated by inhibition of the miR-200 family through epigenetic changes that allows expression of epithelial to mesenchymal transition (EMT) and migration genes, resulting in the migratory phenotype.