Microenvironment and Immunology RORa Suppresses Breast Tumor Invasion by Inducing SEMA3F Expression

Inactivation of tumor suppressors and inhibitory microenvironmental factors is necessary for breast cancer invasion; therefore, identifying those suppressors and factors is crucial not only to advancing our knowledge of breast cancer, but also to discovering potential therapeutic targets. By analyzing gene expression profiles of polarized and disorganized humanmammary epithelial cells in a physiologically relevant three-dimensional (3D) culture system, we identified retinoid orphan nuclear receptor alpha (RORa) as a transcription regulator of semaphorin 3F (SEMA3F), a suppressive microenvironmental factor. We showed that expression of RORa was downregulated in human breast cancer tissue and cell lines, and that reducedmRNA levels of RORa and SEMA3F correlated with poor prognosis. Restoring RORa expression reprogrammed breast cancer cells to form noninvasiveness structures in 3D culture and inhibited tumor growth in nude mice, accompanied by enhanced SEMA3F expression. Inactivation of RORa in nonmalignant human mammary epithelial cells inhibited SEMA3F transcription and impaired polarized acinar morphogenesis. Using chromatin immunoprecipitation and luciferase reporter assays, we showed that transcription of SEMA3F is directly regulated by RORa. Knockdown of SEMA3F in RORa-expressing cancer cells rescued the aggressive 3D phenotypes and tumor invasion. These findings indicate that RORa is a potential tumor suppressor and inhibits tumor invasion by inducing suppressive cell microenvironment. Cancer Res; 72(7); 1728–39. 2012 AACR.