PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D Journal Article


Authors: Toska, E.; Osmanbeyoglu, H. U.; Castel, P.; Chan, C.; Hendrickson, R. C.; Elkabets, M.; Dickler, M. N.; Scaltriti, M.; Leslie, C. S.; Armstrong, S. A.; Baselga, J.
Article Title: PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D
Abstract: Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase a (PI3Kα), are frequently found in estrogen receptor (ER)-positive breast cancer. PI3Kα inhibitors, now in late-stage clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy.We investigated the chromatinbased mechanisms leading to the activation of ER upon PI3Kα inhibition.We found that PI3Kα inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine 4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3Kα inhibition enhances KMT2D activity. These findings uncover a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer.
Journal Title: Science
Volume: 355
Issue: 6331
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science  
Date Published: 2017-03-24
Start Page: 1324
End Page: 1330
Language: English
DOI: 10.1126/science.aah6893
PROVIDER: scopus
PUBMED: 28336670
PMCID: PMC5485411
DOI/URL:
Notes: Article -- Export Date: 2 May 2017 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Maura N Dickler
    200 Dickler
  2. Christina Leslie
    90 Leslie
  3. Pau Castel
    18 Castel
  4. Jose T Baselga
    310 Baselga
  5. Eneda   Toska
    9 Toska
  6. Carmen Jai Hua Chan
    1 Chan