TY - JOUR
T1 - PI3K Pathway Regulates ER-Dependent Transcription in Breast Cancer Through the Epigenetic Regulator KMT2D
AU - Toska, Eneda
AU - Osmanbeyoglu, Hatice U.
AU - Castel, Pau
AU - Chan, Carmen
AU - Hendrickson, Ronald C.
AU - Elkabets, Moshe
AU - Dickler, Maura N.
AU - Scaltriti, Maurizio
AU - Leslie, Christina S.
AU - Armstrong, Scott A.
AU - Baselga, José
N1 - Funding Information:
This work was supported by NIH grant RO1CA190642-01A1, the Breast Cancer Research Foundation, and the Geoffrey Beene Cancer Research Center (to J.B.); National Cancer Institute (NCI) Cancer Center Support Grant P30CA08748 to the Microchemistry and Proteomics Core Laboratory of the Memorial Sloan Kettering Cancer Center; and NIH grants CA66996 and CA140575 to S.A.A. We are also grateful for the support of T. and B. Weinstein. E.T. holds a fellowship from the Terri Brodeur Breast Cancer Foundation. H.U.O. is supported by NCI award K99 CA207871.
PY - 2017/3/24
Y1 - 2017/3/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85016264226&partnerID=8YFLogxK
U2 - 10.1126/science.aah6893
DO - 10.1126/science.aah6893
M3 - מאמר
C2 - 28336670
AN - SCOPUS:85016264226
SN - 0036-8075
VL - 355
SP - 1324
EP - 1330
JO - Science
JF - Science
IS - 6331
ER -
