@article{2d70b602935146dbaee96f9a4e3de60f,
title = "Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer",
abstract = "The 17q23 amplicon is associated with poor outcome in ER+ breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. Here, we interrogate transcriptome data from primary breast tumors and find that among genes in 17q23, PRR11 is a key gene associated with a poor response to therapeutic estrogen suppression. PRR11 promotes estrogen-independent proliferation and confers endocrine resistance in ER+ breast cancers. Mechanistically, the proline-rich motif-mediated interaction of PRR11 with the p85α regulatory subunit of PI3K suppresses p85 homodimerization, thus enhancing insulin-stimulated binding of p110-p85α heterodimers to IRS1 and activation of PI3K. PRR11-amplified breast cancer cells rely on PIK3CA and are highly sensitive to PI3K inhibitors, suggesting that PRR11 amplification confers PI3K dependence. Finally, genetic and pharmacological inhibition of PI3K suppresses PRR11-mediated, estrogen-independent growth. These data suggest ER+/PRR11-amplified breast cancers as a novel subgroup of tumors that may benefit from treatment with PI3K inhibitors and antiestrogens.",
author = "Lee, {Kyung min} and Guerrero-Zotano, {Angel L.} and Alberto Servetto and Sudhan, {Dhivya R} and Lin, {Chang Ching} and Luigi Formisano and Jansen, {Valerie M.} and Paula Gonz{\'a}lez-Ericsson and Sanders, {Melinda E.} and Stricker, {Thomas P.} and Ganesh Raj and Dean, {Kevin M.} and Fiolka, {Reto P} and Cantley, {Lewis C.} and Hanker, {Ariella B.} and Arteaga, {Carlos L.}",
note = "Funding Information: C.L. Arteaga has received research grants from Pfizer, Lilly, and Takeda. He holds minor stock options in Provista and Y-TRAP, and serves or has served in an advisory role to Novartis, Merck, Lilly, Daiichi Sankyo, Taiho Oncology, OrigiMed, Puma Biotechnology, Immunomedics, AstraZeneca, and Sanofi. He is a member of the Scientific Advisory Board (SAB) of the Susan G. Komen Foundation. L.C. Cantley is a founder and member of the SAB and holds equity in Agios Pharmaceuticals and Petra Pharmaceuticals, companies developing drugs for treating cancer. The laboratory of L.C. Cantley also receives funding from Petra. A.B. Hanker receives grant support from Takeda. A.L. Guerrero-Zotano has received grant support from Pfizer and travel support from Pfizer and Roche. V.M. Jansen is a current employee and shareholder of Eli Lilly and Company. Funding Information: This study was supported by NCI Breast SPORE grant P50 CA098131, Vanderbilt-Ingram Cancer Center P30 CA68485, UTSW Simmons Cancer Center P30 CA142543, CPRIT RR170061 grant (C.L.A.), Susan G. Komen Breast Cancer Foundation grant SAC100013 (C.L.A.), grants from the Breast Cancer Research Foundation (C.L.A., L.C. C.), Susan G. Komen Postdoctoral Fellowship PDF17487926 (K.-M.L.), NIH grants R35 CA197588 (L.C.C.), U54 U54CA210184 (L.C.C.), and the Gray Foundation (L.C.C.). We thank Dr. Jennifer A. Pietenpol, Dr. Ben Ho Park, and Dr. Gordon Mills for providing cell lines and materials. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "1",
doi = "10.1038/s41467-020-19291-x",
language = "English (US)",
volume = "11",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}