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DOI | 10.1126/science.aah6893 |
CANCER THERAPY PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D | |
Toska, Eneda1; Osmanbeyoglu, Hatice U.2; Castel, Pau1,3; Chan, Carmen1; Hendrickson, Ronald C.4; Elkabets, Moshe1,5; Dickler, Maura N.6; Scaltriti, Maurizio1,7; Leslie, Christina S.2; Armstrong, Scott A.8,9; Baselga, Jose1,6 | |
2017-03-24 | |
发表期刊 | SCIENCE
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ISSN | 0036-8075 |
EISSN | 1095-9203 |
出版年 | 2017 |
卷号 | 355期号:6331页码:1324-1329 |
文章类型 | Article |
语种 | 英语 |
国家 | USA; Israel |
英文摘要 | 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. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000397082900042 |
WOS关键词 | H3K4 MONOMETHYLATION ; COMPASS FAMILY ; PHASE-I ; FOXA1 ; METHYLTRANSFERASE ; METHYLATION ; DISRUPTION ; MECHANISMS ; CHROMATIN ; STRATEGY |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/195687 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, 1275 York Ave,Box 20, New York, NY 10065 USA; 2.Computat Biol Program, Mem Sloan Kettering Canc Ctr, 1275 York Ave,Box 460, New York, NY 10065 USA; 3.Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, 1450 3rd St, San Francisco, CA 94158 USA; 4.Mem Sloan Kettering Canc Ctr, Microchemistry & Prote Core Lab, New York, NY 10065 USA; 5.Ben Gurion Univ Negev, Shraga Segal Dept Microbiol, Immunol & Genet, Fac Hlth Sci, IL-84105 Beer Sheva, Israel; 6.Dept Med, Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA; 7.Dept Pathol, Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA; 8.Canc Biol & Genet Program, Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA; 9.Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave, Boston, MA 02215 USA |
推荐引用方式 GB/T 7714 | Toska, Eneda,Osmanbeyoglu, Hatice U.,Castel, Pau,et al. CANCER THERAPY PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D[J]. SCIENCE,2017,355(6331):1324-1329. |
APA | Toska, Eneda.,Osmanbeyoglu, Hatice U..,Castel, Pau.,Chan, Carmen.,Hendrickson, Ronald C..,...&Baselga, Jose.(2017).CANCER THERAPY PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D.SCIENCE,355(6331),1324-1329. |
MLA | Toska, Eneda,et al."CANCER THERAPY PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D".SCIENCE 355.6331(2017):1324-1329. |
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