RORα Suppresses Breast Tumor Invasion by Inducing SEMA3F Expression
Open Access
- 1 April 2012
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 72 (7), 1728-1739
- https://doi.org/10.1158/0008-5472.can-11-2762
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. Cancer Res; 72(7); 1728–39. ©2012 AACR.Other Versions
This publication has 60 references indexed in Scilit:
- Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progressionNature Medicine, 2011
- Gene transcriptional networks integrate microenvironmental signals in human breast cancerIntegrative Biology, 2010
- Activation of Aromatase Expression by Retinoic Acid Receptor-related Orphan Receptor (ROR) α in Breast Cancer CellsOnline Journal of Public Health Informatics, 2009
- Sustained activation of STAT5 is essential for chromatin remodeling and maintenance of mammary-specific functionThe Journal of cell biology, 2009
- ABL2/ARG Tyrosine Kinase Mediates SEMA3F-induced RhoA Inactivation and Cytoskeleton Collapse in Human Glioma CellsOnline Journal of Public Health Informatics, 2008
- Extracellular Matrix-regulated Gene Expression Requires Cooperation of SWI/SNF and Transcription FactorsOnline Journal of Public Health Informatics, 2007
- Three-dimensional culture models of normal and malignant breast epithelial cellsNature Methods, 2007
- Genomic and transcriptional aberrations linked to breast cancer pathophysiologiesCancer Cell, 2006
- RORA, a large common fragile site gene, is involved in cellular stress responseOncogene, 2006
- A Functional Genomics Strategy Reveals Rora as a Component of the Mammalian Circadian ClockNeuron, 2004