Epigenetic Regulation of miRNAs and Breast Cancer Stem Cells

Abstract

MicroRNAs have emerged as important targets of chemopreventive strategies in breast cancer. We have found that miRNAs are dysregulated at an early stage in breast cancer, in non-malignant Ductal Carcinoma In Situ. Many dietary chemoprevention agents can act by epigenetically activating miRNA-signaling pathways involved in tumor cell proliferation and invasive progression. In addition, many miRNAs activated via chemopreventive strategies target cancer stem cell signaling and prevent tumor progression or relapse. Specifically, we have found that miRNAs regulate DCIS stem cells, which may play important roles in breast cancer progression to invasive disease. We have shown that chemopreventive agents can directly inhibit DCIS stem cells and block tumor formation in vivo, via activation of tumor suppressor miRNAs.

Breast cancer stem cells as last soldiers eluding therapeutic burn: A hard nut to crack

“…Several evidences show a consensus that CSCs are inherited with long‐term proliferative potential and ability to regenerate tumors with phenotypically heterogeneous cell types. In breast cancer, these cells often indicate characteristics of cells of EMT . Further, EMT state in breast cancer is linked to CSC properties, self‐renewal capabilities, resistance to conventional therapies and post‐treatment recurrence.…”

“…An EMT equips carcinoma to acquire properties of tumor‐initiating cells (TICs). Recently, methods are described to abolish mesenchymal TICs by converting them into epithelial counter parts that show lack of tumor‐initiating ability . The authors reveal that the second messenger, cAMP and the subsequent activation of protein kinase A (PKA) may support mesenchymal‐to‐epithelial transition (MET).…”

“…There is an increasing evidence to support intricacies in molecular mechanisms that drive BCSCs. Among several potential players, non‐protein‐coding RNAs participate in carcinogenesis . These small RNAs such as microRNA's (miRNAs), act as endogenous regulators of gene expression that exert their effect by binding to the 3'‐untranslated region (UTR) of large target messenger RNAs (mRNAs) .…”

“…In a recent report, the notion that BCSCs may show a distinct miRNA expression profile compared to non‐tumorigenic breast cancer cells is widely accepted . These deregulated miRNAs may act as on comiRNAs or as tumor suppressive miRNAs towards self‐renewal, EMT, or stem cell identity maintenance of BCSC community . Besides, potential miRNAs may be involved in increased chemotherapeutic resistance of BCSCs …”

“…Furthermore, several studies have documented that selected miRNAs, such as miRNA‐200c, miRNA‐34a, miRNA‐155 and miRNA‐181 have been linked to maintenance of stem cell like feature in breast cancer and may influence the response to chemotherapy . In addition to deregulation of miRNAs in normal and tumor tissue, BCSCs are reported to display a unique pattern of miRNA signature.…”