期刊
SCIENCE ADVANCES
卷 5, 期 2, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aav5590
关键词
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资金
- Italian Association for Cancer Research [IG-17426]
- Italian Ministry of Instruction and Research (Flagship Project EPIGEN)
- Italian Ministry of Instruction and Research (Flagship Project InterOmics)
- University of Salerno (Fondi FARB 2017)
Breast cancer (BC) resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor alpha (ER alpha) signaling, and ways to block ERa pathway in these tumors are sought after. We identified the H3K79 methyltransferase DOT1L as a novel cofactor of ER alpha in BC cell chromatin, where the two proteins colocalize to regulate estrogen target gene transcription. DOT1L blockade reduces proliferation of hormone-responsive BC cells in vivo and in vitro, consequent to cell cycle arrest and apoptotic cell death, with widespread effects on ER-dependent gene transcription, including ER alpha and FOXA1 gene silencing. Antiestrogen-resistant BC cells respond to DOT1L inhibition also in mouse xenografts, with reduction in ER alpha levels, H3K79 methylation, and tumor growth. These results indicate that DOT1L is an exploitable epigenetic target for treatment of endocrine therapy-resistant ER alpha-positive BCs.
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