Super-enhancer-controlled positive feedback loop BRD4/ERα-RET-ERα promotes ERα-positive breast cancer.
Zao-Zao ZhengLin XiaGuo-Sheng HuJun-Yi LiuYa-Hong HuYu-Jie ChenJia-Yin PengWen-Juan ZhangWen LiuPublished in: Nucleic acids research (2022)
Estrogen and estrogen receptor alpha (ERα)-induced gene transcription is tightly associated with ERα-positive breast carcinogenesis. ERα-occupied enhancers, particularly super-enhancers, have been suggested to play a vital role in regulating such transcriptional events. However, the landscape of ERα-occupied super-enhancers (ERSEs) as well as key ERα-induced target genes associated with ERSEs remain to be fully characterized. Here, we defined the landscape of ERSEs in ERα-positive breast cancer cell lines, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSEs and cognate ERα target genes. RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key ERα target gene of BRD4-regulated ERSEs, which, in turn, is vital for ERα-induced gene transcriptional activation and malignant phenotypes through activating the RAS/RAF/MEK2/ERK/p90RSK/ERα phosphorylation cascade. Combination therapy with BRD4 and RET inhibitors exhibited additive effects on suppressing ERα-positive breast cancer both in vitro and in vivo, comparable with that of standard endocrine therapy tamoxifen. Furthermore, combination therapy re-sensitized a tamoxifen-resistant ERα-positive breast cancer cell line to tamoxifen treatment. Taken together, our data uncovered the critical role of a super-enhancer-associated positive feedback loop constituting BRD4/ERα-RET-ERα in ERα-positive breast cancer, and suggested that targeting components in this loop would provide a new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
Keyphrases
- estrogen receptor
- positive breast cancer
- breast cancer cells
- endoplasmic reticulum
- transcription factor
- combination therapy
- stem cells
- gene expression
- signaling pathway
- genome wide
- electronic health record
- primary care
- cell proliferation
- mesenchymal stem cells
- oxidative stress
- machine learning
- copy number
- bone marrow
- big data
- diabetic rats
- deep learning
- single molecule
- sensitive detection
- replacement therapy
- heat shock protein
- quantum dots