RORα suppresses breast tumor invasion through inducing SEMA3F expression
Menée sur un système tridimensionnel de culture cellulaire, cette étude met en évidence un mécanisme par lequel, en induisant l'expression du gène SEMA3F, le gène RORα est susceptible de jouer un rôle de suppresseur de tumeurs dans le cancer du sein
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 human mammary epithelial cells (HMECs) in a physiologically relevant three-dimensional (3D) culture system, we identified retinoid orphan nuclear receptor alpha (RORα) as a transcription regulator of semaphorin 3F (SEMA3F), a suppressive microenvironmental factor. We showed that expression of RORα was down-regulated in human breast cancer tissue and cell lines, and that reduced mRNA levels of RORα and SEMA3F correlated with poor prognosis. Restoring RORα expression reprogrammed breast cancer cells to form non-invasiveness structures in 3D culture and inhibited tumor growth in nude mice, accompanied by enhanced SEMA3F expression. Inactivation of RORα in non-malignant HEMCs 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 RORα. Knockdown of SEMA3F in RORα-expressing cancer cells rescued the aggressive 3D phenotypes and tumor invasion. These findings indicate that RORα is a potential tumor suppressor and inhibits tumor invasion by inducing suppressive cell microenvironment.