Format

Send to

Choose Destination
Science. 2017 Mar 24;355(6331):1324-1330. doi: 10.1126/science.aah6893.

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

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
2
Computational Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 460, New York, NY 10065, USA.
3
Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA.
4
Microchemistry and Proteomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
6
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
7
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
9
Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.

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.

PMID:
28336670
PMCID:
PMC5485411
DOI:
10.1126/science.aah6893
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center