Abstract 3310: microRNAs regulate the transition between EMT and MET breast cancer stem cell states

Abstract

Abstract Recent studies have suggested similarities between cancer stem cells and the epithelial mesenchymal transition (EMT) state. In contrast, other studies suggest that these “states” are mutually exclusive. Our studies suggest that these divergent views may be explained by the existence of multiple stem cell states, which are regulated by microRNAs. Utilizing primary breast tissue and established cell lines, we demonstrate that both normal and malignant breast stem cells exist in distinct, inter-convertible states. The EMT-like state is characterized by expression of vimentin and N-cadherin, slug, snail and twist transcription factors. EMT-like CSCs have a mesenchymal morphology, are largely quiescent, invasive and characterized by expression of the CSC markers CD44+CD24− and are EpCAM−CD49f+. In contrast, the MET (mesenchymal epithelial transition) state of CSCs is characterized by an epithelial morphology and expression of E-cadherin and EpCAM. MET-like CSCs undergo self-renewal and express the CSC marker Aldehyde dehydrogenase (ALDH) and are EpCAM+CD49F+. A subpopulation of cells expressing both CD44+CD24− and ALDH may represent cells in transition between these states. This transition is regulated by signals in the microenvironment which in turn modulate microRNA networks. Expression induction of mir100 in MCF10A cells and several cancer cell lines resulted in a decrease of ALDH-positive CSC population with a concomitant increase in the CD24−CD44+ population accompanied by induction of EMT. We demonstrated mir100 effects are mediated by targeting BMPR2, SMARCA5 and SMARCD1, all of which may contribute to induction of EMT. Moreover, we show that mir100 overexpression induces cellular quiescence as shown by Ki67 and Brdu staining. Induction of mir100 expression immediately upon orthotopic implantation or after the tumors are established significantly reduced the subsequent tumor growth in NOD/SCID mice. In contrast of overexpression of mir100 stimulates cell invasion in vitro matrigel assay. The existence of multiple cancer stem cell states has important implications for understanding stem cell plasticity as well as tumor growth and metastasis. In addition, the existence of these states has implications for the development of CSC-targeting therapeutics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3310. doi:1538-7445.AM2012-3310