A super enhancer-controlled BRD4/ERa-RET-ERa positive feedback loop promotes ERa-positive breast cancer [GRO-seq]

Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERa)-positive breast carcinogenesis. ERa-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERa-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERa-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERa-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERa-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERa phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERa-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERa-RET-ERa positive feedback loop in ERa-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERa-positive breast cancer in the clinic. Overall design: 4 GRO-seq