Abstract
Abstract We previously reported that dietary genistein significantly inhibits mammary tumor growth and metastasis of estrogen receptor (ER) (-) MDA-MB-435 metastatic cancer cells in immunocompromised mice. The purpose of the present study is to investigate the molecular mechanisms of genistein in ER (-) breast cancer cells. We report that at low physiologically relevant concentrations, genistein significantly inhibits cell growth and induces apoptosis in MDA-MB-435 and Hs578t breast cancer cells. To investigate the mechanism by which genistein regulates cancer cell viability, a panel of microRNAs (miRNAs) were tested for differential expression in response to genistein treatment. We found that miR-155, a designated oncomiR in breast cancer, is significantly downregulated by genistein in MDA-MB-435 and Hs578t cells. Concomitantly, pro-apoptotic and anti-cell proliferative miR-155 targets FOXO3, PTEN, casein kinase (CK1alpha), and p27 are upregulated by genistein. Moreover, the CK1alpha target beta catenin is downregulated in the MDA-MB-435 cells, thus further contributing to the anticancer effects of genistein by inhibiting wnt signaling. Stable ectopic expression of miR-155 in MDA-MB-435 and Hs578t cells decreases the inhibitory effect of genistein on cell viability, and abrogates the effect of genistein on apoptosis and expression of pro-apoptotic proteins. Therefore, genistein acts as a potential anti breast cancer therapeutic via downregulation of miR-155, a critical suppressor of apoptosis. This study was sponsored by United States Army/BCRP W81XWH-11-1-0199 (to CDP), NIH/NIGMS SC3GM084824 (to SD), NIH/NIGMS G12RR035051 (to UPR MSC), and NIH/NIGMS G12RR003035 and Title V PPOHA US Department of Education #P031M105050 (to UCC). Citation Format: Columba de la Parra, Linette Castillo-Pichardo, Luis A. Cubano, George A. Calin, Suranganie Dharmawardhane. Therapeutic potential of genistein via targeting the microRNA miR-155 in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A057.
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