Abstract 13: Regulation of breast cancer stem cells by miR-93

Abstract

Abstract There is increasing evidence that the growth and metastasis of many tumors, including breast cancer, are driven by a cellular population displaying stem cell properties. Like their normal counterparts, these breast cancer stem cells may be regulated by MicroRNAs (miRNAs). We have previously demonstrated that breast cancer cell lines contain subpopulations with stem cell properties that can be isolated by virtue of their expression of Aldehyde dehydrogenase (ALDH) as assessed by the Aldefluor assay. We compared miRNA expression in Aldefluor-positive and Aldefluor-negative populations in a series of five breast cancer cell lines. We identified specific miRNA expression profiles for each population. Among the differentially expressed miRNAs was miR-93 whose expression was significantly increased in Aldefluor-negative compared to Aldefluor-positive populations. To confirm the regulation of miR-93 during cell differentiation we constructed a miR-93 sensor tagged with GFP and demonstrated that sensor-positive (miR-93-negative) cells had significantly increased tumor initiating capacity in NOD/SCID mouse xenografts compared to sensor-negative (miR-93-positive cells). Furthermore, miR-93-negative cells gave rise to tumors containing both miR-93-negative and miR-93-positive cell populations. Utilizing a tetracycline inducible lentivirus driving miR-93 expression, we found that induction of miR-93 expression decreased the ALDH-positive population in vitro as well as in mouse xenografts where this reduction was associated with decreased tumor growth. Furthermore, induction of miR-93 expression immediately upon orthotopic implantation or intracardiac injection completely blocked subsequent tumor growth and metastasis formation. These studies demonstrate that miR-93 plays a functional role in the self-renewal and differentiation of breast cancer stem cells. Furthermore, the TET-inducible miR-93 system allows for the controlled regulation of cancer stem cell function providing a valuable model to simulate the effects of CSC-directed therapies on breast cancer growth and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 13.