title: RORα suppresses breast tumor invasion by inducing SEMA3F expression.
abstract: 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 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 downregulated 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 noninvasiveness structures in 3D culture and inhibited tumor growth in nude mice, accompanied by enhanced SEMA3F expression. Inactivation of RORα 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 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.
authors.affiliation: Markey Cancer Center, and the Department of Molecular and Biomedical Pharmacology, Surgery, and Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Gaofeng
authors.initials: G
authors.lastname: Xiong
authors.forename: Chi
authors.initials: C
authors.lastname: Wang
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
authors.forename: Binhua P
authors.initials: BP
authors.lastname: Zhou
authors.forename: Ren
authors.initials: R
authors.lastname: Xu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology* / Q000473:pathology; D045744:Cell Line, Tumor; D016764:Cell Polarity; D060833:Cellular Microenvironment; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D011379:Prognosis; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; C491230:SEMA3F protein, human; D025521:Tumor Suppressor Proteins