MicroRNA93 Regulates Proliferation and Differentiation of Normal and Malignant Breast Stem Cells

Abstract

MicroRNAs (miRNAs) play important roles in normal cellular differentiation and oncogenesis. microRNA93 (mir-93), a member of the mir106b-25 cluster, located in intron 13 of the MCM7 gene, although frequently overexpressed in human malignancies may also function as a tumor suppressor gene. Using a series of breast cancer cell lines representing different stages of differentiation and mouse xenograft models, we demonstrate that mir-93 modulates the fate of breast cancer stem cells (BCSCs) by regulating their proliferation and differentiation states. In “claudinlow” SUM159 cells, expression of mir-93 induces Mesenchymal-Epithelial Transition (MET) associated with downregulation of TGFβ signaling and downregulates multiple stem cell regulatory genes, including JAK1, STAT3, AKT3, SOX4, EZH1, and HMGA2, resulting in cancer stem cell (CSC) depletion. Enforced expression of mir-93 completely blocks tumor development in mammary fat pads and development of metastases following intracardiac injection in mouse xenografts. The effect of mir-93 on the CSC population is dependent on the cellular differentiation state, with mir-93 expression increasing the CSC population in MCF7 cells that display a more differentiated “luminal” phenotype. mir-93 also regulates the proliferation and differentiation of normal breast stem cells isolated from reduction mammoplasties. These studies demonstrate that miRNAs can regulate the states and fates of normal and malignant mammary stem cells, findings which have important biological and clinical implications.

Regulation of miR106b cluster through the RB pathway

“…[14][15][16] For example, deregulated miRNA expression has been implicated in aberrant proliferation, genome stability and epithelial-mesenchymal transition. [17][18][19] Analyses of miRNA expression in breast cancer tumor specimens have demonstrated association with specific breast cancer subtypes. Additionally, specific miRNA species are correlated with specific facets of breast cancer biology and prognosis.…”

Association of microRNA-93, 190, 200b and Receptor Status in Core Biopsies from Stage III Breast Cancer Patients

“…In summary, in-depth analysis of data from cell lines, mouse and human clinical studies produced further evidence that miRNA-93 seems to be a therapeutic target in breast cancer although these observations need to be validated (Blenkiron et al, 2007;Fang et al, 2012;Liu et al, 2012). and ER,PR,and HER2 expression In this study, we failed to demonstrate statistically significant differences in miRNA-190 and 200b levels in core biopsies of breast cancer patients with a variety of ER, PR, and HER2 expression.…”

“…Blenkiron et al (2007) correlating with tumor subtype ( p < 0.05), ER status ( p < 0.01), and grade ( p < 0.001). Liu et al (2012) using a series of breast cancer cell lines representing different stages of differentiation and mouse xenograft models, showed convincingly that miRNA-93 modulates the fate of breast cancer stem cells (BCSCs). Recent evidence suggests that BCSCs may contribute to tumor metastasis, treatment resistance, and relapse.…”

“…These particular miRNAs were selected on the basis of previous reports in the literature, the miRNA database, and communications from breast cancer conferences. They represent a broad range of epigenetic pathways involved in migration, invasion, receptor status, epithelialto-mesenchymal transition, cancer dormancy, switch to the fast growing phenotype, drug resistance, etc (Blenkiron et al, 2007;Lowery et al, 2008;Fang et al, 2012;Liu et al, 2012;Manavalan et al, 2013;Lehmann, 2014;Li et al, 2014;McDermott et al, 2014;www.mirbase.org). We also used unpublished data of TaqMan Low Density Arrays from our previous research.…”

Pancreatic Cancer Stem Cells

“…MicroRNAs (miRNAs), small non-coding RNAs whose critical roles have been confirmed in development, have also emerged as significant regulators of CSCs in types of malignancies and have been substantiated as inspiring potential targets for cancer therapy [72,[80][81][82][83][84][85]. Downregulated expression of micro-RNA494 (miR494) mediated by the loss of SMAD4, as demonstrated in a recent study, was correlated to the enhanced level of FoxM1 and the increased activity of beta-catenin signaling in pancreatic cancer cells [86].…”