PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D.
Activating mutations inPIK3CA, 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.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
Eneda
0000-0002-8974-9792
E
Toska
Computational Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 460, New York, NY 10065, USA.
Hatice U
HU
Osmanbeyoglu
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.|Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA.
Pau
0000-0002-4972-4347
P
Castel
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.
Carmen
0000-0001-9086-6622
C
Chan
Microchemistry and Proteomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Ronald C
0000-0002-6899-7287
RC
Hendrickson
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.|The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
Moshe
0000-0003-3634-9098
M
Elkabets
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Maura N
MN
Dickler
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Maurizio
0000-0002-5522-1447
M
Scaltriti
Computational Biology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 460, New York, NY 10065, USA.
Christina S
0000-0002-4571-5910
CS
Leslie
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Scott A
0000-0002-9099-4728
SA
Armstrong
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, NY 10065, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
José
0000-0003-1361-4063
J
Baselga
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000628:therapy*; D002843:Chromatin / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D057809:HEK293 Cells; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D053858:Metabolic Networks and Pathways; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D002843:Chromatin; D004268:DNA-Binding Proteins; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; C083400:PBX1 protein, human; D008780:Methyltransferases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D008239:Lysine