Oncogene, 2018-08, Vol.37 (34), p.4692-4710
2018
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- Autor(en) / Beteiligte
- Titel
- KMT2C mediates the estrogen dependence of breast cancer through regulation of ERα enhancer function
- Ist Teil von
- Oncogene, 2018-08, Vol.37 (34), p.4692-4710
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0950-9232eISSN: 1476-5594DOI: 10.1038/s41388-018-0273-5Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6107480
- Format
- –
- Schlagworte
- Animals, Antiestrogens, Breast cancer, Breast Neoplasms - metabolism, 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, Humans, Mammary gland, MCF-7 Cells, Methyltransferase, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neoplasm Proteins - metabolism, Progression-Free Survival, Signal Transduction - physiology