Soy Isoflavone Genistein-Mediated Downregulation of miR-155 Contributes to the Anticancer Effects of Genistein

ABSTRACT

We previously reported that dietary genistein inhibits mammary tumor growth and metastasis of the highly metastatic MDA-MB-435 cancer cells in immunocompromised mice. The purpose herein was to characterize the role of the novel oncogenic microRNA (miRNA) miR-155 in the anticancer effects of genistein in metastatic breast cancer. The effect of genistein was determined on breast cancer cell viability, apoptosis, and expression of miR-155 and its targets. At low physiologically relevant concentrations, genistein inhibits cell viability and induces apoptosis in metastatic MDA-MB-435 and Hs578t breast cancer cells, without affecting the viability of nonmetastatic MCF-7 breast cancer cells. In parallel with reduced cell viability, miR-155 is downregulated, whereas proapoptotic and anticell proliferative miR-155 targets FOXO3, PTEN, casein kinase, and p27 are upregulated in MDA-MB-435 and Hs578t cells in response to genistein treatment. However, miR-155 levels remain unchanged in response to genistein in the MCF-7 cells. Ectopic expression of miR-155 in MDA-MB-435 and Hs578t cells decreases the effects of genistein on cell viability and abrogates the effects of genistein on apoptosis and expression of proapoptotic genes. Therefore, genistein-mediated downregulation of miR-155 contributes to the anticancer effects of genistein in metastatic breast cancer.

Funding

This work was sponsored by the United States Army/Breast Cancer Research Program W81XWH-11-1-0199 to CDP; National Institutes of Health (NIH)/National Institute of General Medical Sciences SC3GM084824 to SD; NIH/National Institute on Minority Health and Health Disparities (NIMHD) G12RR035051 to the University of Puerto Rico Medical Sciences Campus; and NIH/NIMHD G12RR003035, NIH/NIMHHD Research Centers in Minority Institutions (RCMI) 8G12MD007583, Title V PPOHA P031S130068 from United States Department of Education, and Title V Promoting Postbaccalaureate Opportunities for Hispanic Americans Program United States Department of Education P031M105050 to Universidad Central del Caribe.