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

Eneda Toska1, Hatice U Osmanbeyoglu2, Pau Castel1,3

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.

Science (New York, N.Y.)
|March 25, 2017
PubMed

Insights

Targeting PIK3CA in breast cancer is limited by increased estrogen receptor activity. This study reveals PI3Kα inhibition opens chromatin, activating ER via KMT2D, suggesting epigenetic therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Activating PIK3CA mutations are common in estrogen receptor (ER)-positive breast cancer.
  • PI3Kα inhibitors are in clinical development but face efficacy limitations due to compensatory ER activation.

Purpose of the Study:

  • To investigate the chromatin-based mechanisms driving ER activation following PI3Kα inhibition.
  • To identify key regulators involved in ER reactivation upon PI3Kα targeting.

Main Methods:

  • Utilized breast cancer models and clinical samples to analyze chromatin accessibility.
  • Investigated the role of KMT2D (histone methyltransferase) in ER recruitment and activation.
  • Examined the interplay between AKT, KMT2D, and PI3Kα signaling pathways.

Main Results:

  • PI3Kα inhibition induced an open chromatin state at ER target loci.
  • KMT2D was essential for the recruitment and activation of FOXA1, PBX1, and ER.
  • AKT-mediated phosphorylation of KMT2D inhibited its activity, while PI3Kα inhibition enhanced KMT2D activity.

Conclusions:

  • PI3Kα inhibition activates ER through epigenetic mechanisms involving KMT2D.
  • Posttranslational modification of epigenetic regulators controls ER activation.
  • These findings support the development of epigenetic therapies for ER-positive breast cancer.

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