Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer

Kyung-min Lee, Angel L. Guerrero-Zotano, Alberto Servetto, Dhivya R. Sudhan, Chang-Ching Lin, Luigi Formisano, Valerie M. Jansen, Paula González-Ericsson, Melinda E. Sanders, Thomas P. Stricker, Ganesh Raj, Kevin M. Dean, Reto Fiolka, Lewis C. Cantley, Ariella B. Hanker and Carlos L. Arteaga ()
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Kyung-min Lee: University of Texas Southwestern Medical Center
Angel L. Guerrero-Zotano: Vanderbilt University Medical Center
Alberto Servetto: University of Texas Southwestern Medical Center
Dhivya R. Sudhan: University of Texas Southwestern Medical Center
Chang-Ching Lin: University of Texas Southwestern Medical Center
Luigi Formisano: Vanderbilt University Medical Center
Valerie M. Jansen: Vanderbilt University Medical Center
Paula González-Ericsson: Vanderbilt University Medical Center
Melinda E. Sanders: Vanderbilt University Medical Center
Thomas P. Stricker: Vanderbilt University Medical Center
Ganesh Raj: University of Texas Southwestern Medical Center
Kevin M. Dean: University of Texas Southwestern Medical Center
Reto Fiolka: University of Texas Southwestern Medical Center
Lewis C. Cantley: Weill Cornell Medicine College
Ariella B. Hanker: University of Texas Southwestern Medical Center
Carlos L. Arteaga: University of Texas Southwestern Medical Center

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19291-x

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