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

• Published in: Oncogene 2018-08, Vol.37 (34), p.4692-4710
• Main Authors: Gala, Kinisha, Li, Qing, Sinha, Amit, Razavi, Pedram, Dorso, Madeline, Sanchez-Vega, Francisco, Chung, Young Rock, Hendrickson, Ronald, Hsieh, James J., Berger, Michael, Schultz, Nikolaus, Pastore, Alessandro, Abdel-Wahab, Omar, Chandarlapaty, Sarat
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/51; 13/89; 38; 38/1; 38/23; 38/39; 38/91; 631/337/176; 631/67/1347; Animals; Antiestrogens; Apoptosis; Breast cancer; Breast Neoplasms - metabolism; Cell Biology; Cell Line; Cell Line, Tumor; Cell proliferation; Cell Proliferation - physiology; Clonal deletion; DNA-Binding Proteins - metabolism; Enhancers; Estrogen Receptor alpha - metabolism; Estrogen receptors; Estrogens - metabolism; Female; Gene expression; Gene Expression Regulation, Neoplastic - physiology; HEK293 Cells; Hepatocyte Nuclear Factor 3-alpha - metabolism; Hormone replacement therapy; Human Genetics; Humans; Internal Medicine; Mammary gland; MCF-7 Cells; Medicine; Medicine & Public Health; Methyltransferase; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Proteins - metabolism; Oncology; Progression-Free Survival; Signal Transduction - physiology
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0273-5

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.