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Oncogene. 2018 Aug;37(34):4692-4710. doi: 10.1038/s41388-018-0273-5. Epub 2018 May 14.

KMT2C mediates the estrogen dependence of breast cancer through regulation of ERα enhancer function.

Author information

1
Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, USA.
2
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA.
3
Basepair, Inc, New York, USA.
4
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
5
Microchemistry and Proteomics Core Facility, Memorial Sloan Kettering Cancer Center, New York, USA.
6
Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, USA.
7
Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, USA. chandars@mskcc.org.
8
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA. chandars@mskcc.org.
9
Weill Cornell Medical College, New York, USA. chandars@mskcc.org.

Abstract

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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