Journal
MOLECULAR CANCER RESEARCH
Volume 17, Issue 12, Pages 2356-2368Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-19-0393
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Funding
- NIH/NIDDK [DK058110]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RP160319, RP190236]
- Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment
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The bromodomain family member proteins (BRD; BET proteins) are key coregulators for estrogen receptor alpha (ER alpha)-mediated transcriptional enhancers. The use of BRD-selective inhibitors has gained much attention as a potential treatment for various solid tumors, including ER-positive breast cancers. However, the roles of individual BET family members have largely remained unexplored. Here, wedescribe the role of BRDs in estrogen (E2)-dependent gene expression in ER alpha-positive breast cancer cells. We observed that chemical inhibition of BET family proteins with JQ1 impairs E2-regulated gene expression and growth in breast cancer cells. In addition, RNAi-mediated depletion of each BET family member (BRDs 2, 3, and 4) revealed partially redundant roles at ER alpha enhancers and for target gene transcription. Furthermore, we found a unique role of BRD3 as a molecular sensor of total BET family protein levels and activity through compensatory control of its own protein levels. Finally, we observed that BRD3 is recruited to a subset of ER alpha-binding sites (ERBS) that are enriched for active enhancer features, located in clusters of ERBSs likely functioning as super enhancers, and associated with highly E2-responsive genes. Collectively, our results illustrate a critical and specific role for BET family members in ER alpha-dependent gene transcription.
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