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
Notes: Article -- Export Date: 4 September 2018 -- Source: Scopus
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MSK Authors
  1. Michael Forman Berger
    373 Berger
  2. Nikolaus D Schultz
    193 Schultz
  3. Young Rock Chung
    46 Chung
  4. Kinisha Pankaj Gala
    2 Gala
  5. Pedram Razavi
    23 Razavi
  6. Alessandro   Pastore
    20 Pastore
  7. Madeline Anne Dorso
    2 Dorso
  8. QING LI
    2 LI