Retinoic acid receptor-related orphan nuclear receptor alpha (RORα) is a potent tumor suppressor that reduces cell proliferation and inhibits tumor growth. However, the molecular mechanism by which it inhibits cell proliferation remains unknown. We demonstrate a noncanonical nuclear receptor pathway in which RORα binds to E2F1 to inhibit cell cycle progression. We showed that RORα bound to the heptad repeat and marked box region of E2F1 and suppressed E2F1-regulated transcription in epithelial cells. Binding of RORα inhibited E2F1 acetylation and its DNA-binding activity by recruiting histone deacetylase 1 (HDAC1) to the protein complexes. Knockdown of HDAC1 or inhibition of HDAC activity at least partially rescued transcription factor activity of E2F1 that was repressed by RORα. Importantly, RORα levels were increased in mammary ducts compared to terminal end buds and inversely correlated with expression of E2F1 target genes and cell proliferation. Silencing RORα in mammary epithelial cells significantly enhanced cell proliferation in the ductal epithelial cells and promoted side branching of the mammary ducts. These results reveal a novel link between RORα and E2F1 in regulating cell cycle progression and mammary tissue morphogenesis.

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Published in Molecular and Cellular Biology, v. 34, no. 16, p. 3066-3075.

Copyright © 2014, American Society for Microbiology. All Rights Reserved.

The copyright holders have granted the permission for posting the article here.

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Funding Information

This study was supported by grants from the ACS (IRG 85-001-22 to R. Xu) and AHA (12SDG8600000 to R. Xu). This work was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (grant UL1TR000117).

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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