PI3K Pathway Regulates ER-Dependent Transcription in Breast Cancer Through the Epigenetic Regulator KMT2D

Eneda Toska, Hatice U. Osmanbeyoglu, Pau Castel, Carmen Chan, Ronald C. Hendrickson, Moshe Elkabets, Maura N. Dickler, Maurizio Scaltriti, Christina S. Leslie, Scott A. Armstrong, José Baselga

Research output: Contribution to journalArticlepeer-review

139 Scopus citations

Abstract

Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase α (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 chromatin-based 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.
Original languageEnglish
Pages (from-to)1324-1330
Number of pages7
JournalScience
Volume355
Issue number6331
DOIs
StatePublished - 24 Mar 2017

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