Abstract 3079: Estrogen signaling promotes cancer stem cell expansion via microRNA-140 targeting of pluripotency-associated factor SOX2 in ERα positive breast cancer cells.

Abstract

Abstract Multiple reports indicate that the prospective tumor suppressor miR-140 is down regulated in breast tumors compared to normal breast tissues; however, the role of miR-140 in breast tumorigenesis remains unclear. We have identified a novel target for miR-140 in mammary epithelium, the core pluripotency transcription factor SOX2. It is well known that SOX2 regulates the self-renewal of embryonic stem cells, however, less is known concerning possible oncogenic roles of SOX2 in breast cancer. We found that miR-140 and SOX2 target mRNA exhibited inverse expression in breast tumors and normal breast tissues, which was also correlated with estrogen receptor alpha (ERα) status. We investigated the role of ERα signaling in the regulation of miR-140 and SOX2 in breast tumors and found that estrogen stimulation resulted in decreased miR-140 and increased SOX2 expression in mammary epithelium and breast cancer cells. We performed bioinformatics promoter analyses of the miR-140 promoter revealing several predicted estrogen response elements (ERE) in the miR-140 promoter. We examined estrogen-induced activation of these prospective EREs using luciferase reporters for a miR-140 promoter deletion series. Furthermore, we used chromatin-immunoprecipitation to reveal that ERα binds to an ERE flanking the miR-140 promoter, consequently suppressing miR-140 transcription. As estrogen signaling was previously implicated in the regulation of breast cancer stem cells (CSCs), we investigated whether the miR-140/SOX2 pathway might provide a mechanistic link between ERα signaling and CSC maintenance. We found that forced activation of the miR-140/SOX2 pathway decreased mammosphere formation (a surrogate measure of CSC self-renewal) and opposed estrogen-induced expansion of the well-characterized CD44(high)/CD24(low) CSC subpopulation in ERα+ breast cancer cells. These results indicate that an ERα/miR-140/SOX2 pathway critically regulates breast CSC maintenance in ERα+ breast tumors. Citation Format: Yongshu Zhang, Gabriel L. Eades, Yuan Yao, Qinglin Li, Qun Zhou. Estrogen signaling promotes cancer stem cell expansion via microRNA-140 targeting of pluripotency-associated factor SOX2 in ERα positive breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3079. doi:10.1158/1538-7445.AM2013-3079