Synapse - 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 Journal Article

Authors:	Gala, K.; Li, Q.; Sinha, A.; Razavi, P.; Dorso, M.; Sanchez-Vega, F.; Chung, Y. R.; Hendrickson, R.; Hsieh, J. J.; Berger, M.; Schultz, N.; Pastore, A.; Abdel-Wahab, O.; Chandarlapaty, S.
Article Title:	KMT2C mediates the estrogen dependence of breast cancer through regulation of ERα enhancer function
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. © 2018, The Author(s).
Journal Title:	Oncogene
Volume:	37
Issue:	34
ISSN:	0950-9232
Publisher:	Nature Publishing Group
Date Published:	2018-08-23
Start Page:	4692
End Page:	4710
Language:	English
DOI:	10.1038/s41388-018-0273-5
PROVIDER:	scopus
PMCID:	PMC6107480
PUBMED:	29755131
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85046806280&doi=10.1038%2fs41388-018-0273-5&partnerID=40&md5=d18b7a0411b145d0e2cac6ee101b5d55
Notes:	Article -- Export Date: 4 September 2018 -- Source: Scopus