KMT2C mediates the estrogen dependence of breast cancer through regulation of ERα enhancer function.
KMT2C mediates the estrogen dependence of breast cancer through regulation of ERα enhancer function.
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DOI：
10.1038/s41388-018-0273-5
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发表时间：
2018-08
期刊：
影响因子：
8
通讯作者：
Chandarlapaty S
中科院分区：
文献类型：
--
作者：
Gala K;Li Q;Sinha A;Razavi P;Dorso M;Sanchez-Vega F;Chung YR;Hendrickson R;Hsieh JJ;Berger M;Schultz N;Pastore A;Abdel-Wahab O;Chandarlapaty S
雌激素受体α (ERα)是一种配体激活的核受体，在包括乳腺源性癌在内的特定癌症细胞类型中指导增殖和分化。ERα的这些主要调控功能需要反式作用元件，如先锋因子FOXA1，以建立有利于ERα控制的基因组景观。在这里，我们发现H3K4甲基转移酶KMT2C是激素驱动的ERα活性和乳腺癌增殖所必需的。KMT2C敲低抑制雌激素依赖基因的表达，导致ERα增强子上H3K4me1和H3K27ac选择性丢失。相应地，KMT2C缺失会损害雌激素驱动的乳腺癌增殖，但对ER-乳腺细胞没有影响。虽然KMT2C缺失会破坏雌激素驱动的增殖，但在激素缺乏的情况下，它反而会促进肿瘤的生长。因此，KMT2C是er阳性乳腺癌中最常见的突变基因之一，KMT2C缺失与抗雌激素治疗的无进展生存期显著缩短相关。从治疗的角度来看，kmt2c耗尽的细胞产生激素依赖性，保留对ERα的依赖性，对ERα拮抗剂表现出持续的敏感性。我们得出结论，KMT2C是ERα活性的关键调节因子，其缺失使乳腺癌增殖与激素丰富分离。
Estrogen receptor alpha (ERα) is a ligand-activated nuclear receptor that directs proliferation and differentiation in selected cancer cell types including mammary-derived carcinomas. These master-regulatory functions of ERα require trans-acting elements such as the pioneer factor FOXA1 to establish a genomic landscape conducive to ERα control. Here, we identify the H3K4 methyltransferase KMT2C as necessary for hormone-driven ERα activity and breast cancer proliferation. KMT2C knockdown suppresses estrogen-dependent gene expression and causes H3K4me1 and H3K27ac loss selectively at ERα enhancers. Correspondingly, KMT2C loss impairs estrogen-driven breast cancer proliferation but has no effect on ER- breast cells. Whereas KMT2C loss disrupts estrogen-driven proliferation, it conversely promotes tumor outgrowth under hormone-depleted conditions. In accordance, KMT2C is one of the most frequently mutated genes in ER-positive breast cancer with KMT2C deletion correlating with significantly shorter progression-free survival on anti-estrogen therapy. From a therapeutic standpoint, KMT2C-depleted cells that develop hormone-independence retain their dependence on ERα, displaying ongoing sensitivity to ERα antagonists. We conclude that KMT2C is a key regulator of ERα activity whose loss uncouples breast cancer proliferation from hormone abundance.
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影响因子：
64.8
作者：
Ellis, Matthew J.;Ding, Li;Shen, Dong;Luo, Jingqin;Suman, Vera J.;Wallis, John W.;Van Tine, Brian A.;Hoog, Jeremy;Goiffon, Reece J.;Goldstein, Theodore C.;Ng, Sam;Lin, Li;Crowder, Robert;Snider, Jacqueline;Ballman, Karla;Weber, Jason;Chen, Ken;Koboldt, Daniel C.;Kandoth, Cyriac;Schierding, William S.;McMichael, Joshua F.;Miller, Christopher A.;Lu, Charles;Harris, Christopher C.;McLellan, Michael D.;Wendl, Michael C.;DeSchryver, Katherine;Allred, D. Craig;Esserman, Laura;Unzeitig, Gary;Margenthaler, Julie;Babiera, G. V.;Marcom, P. Kelly;Guenther, J. M.;Leitch, Marilyn;Hunt, Kelly;Olson, John;Tao, Yu;Maher, Christopher A.;Fulton, Lucinda L.;Fulton, Robert S.;Harrison, Michelle;Oberkfell, Ben;Du, Feiyu;Demeter, Ryan;Vickery, Tammi L.;Elhammali, Adnan;Piwnica-Worms, Helen;McDonald, Sandra;Watson, Mark;Dooling, David J.;Ota, David;Chang, Li-Wei;Bose, Ron;Ley, Timothy J.;Piwnica-Worms, David;Stuart, Joshua M.;Wilson, Richard K.;Mardis, Elaine R.
通讯作者：
Mardis, Elaine R.
影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
30.8
作者：
Carroll, Jason S.;Meyer, Clifford A.;Brown, Myles
通讯作者：
Brown, Myles
影响因子：
6.6
作者：
Kannengiesser, Caroline;Spatz, Alain;Bressac-de Paillerets, Brigitte
通讯作者：
Bressac-de Paillerets, Brigitte
影响因子：
45.3
作者：
Gutierrez, MC;Detre, S;Dowsett, M
通讯作者：
Dowsett, M