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

Oncogene
Kinisha GalaSarat Chandarlapaty

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 ...Continue Reading

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Mar 14, 2019·Endocrine-related Cancer·Suzan StellooWilbert Zwart
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Datasets Mentioned

BETA
GSE100328

Methods Mentioned

BETA
acetylation
immunoprecipitation
electrophoresis
transfection
PCR
ChIP
ChIP-seq
genotyping
biopsy

Clinical Trials Mentioned

NCT01775072

Software Mentioned

DESeq2
HOMER
STAR
Softmax Pro
R package
MaxQuant
METABRIC
Basepair
IMPACT
Picard

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