期刊
SCIENCE
卷 355, 期 6331, 页码 1324-1329出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aah6893
关键词
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资金
- NIH [RO1CA190642-01A1, CA66996, CA140575]
- Breast Cancer Research Foundation
- Geoffrey Beene Cancer Research Center
- National Cancer Institute (NCI) Cancer Center Support Grant [P30CA08748]
- NCI [K99 CA207871]
- Novartis Pharmaceuticals
- Epizyme
- Imago Biosciences
- Vitae Pharmaceuticals
Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase alpha (PI3K alpha), are frequently found in estrogen receptor (ER)-positive breast cancer. PI3Ka inhibitors, now in late-stage clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3K alpha inhibition. We found that PI3Ka inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine 4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3K alpha inhibition enhances KMT2D activity. These findings uncover a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer.
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