Proline Rich 11 (PRR11) Overexpression Amplifies PI3K Signaling and Promotes Antiestrogen Resistance in Breast Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Oct 31

PMID 33127913

Citations 24

Authors

Kyung-Min Lee

Angel L Guerrero-Zotano

Alberto Servetto

Dhivya R Sudhan

Chang-Ching Lin

Luigi Formisano

Valerie M Jansen

Paula Gonzalez-Ericsson

Melinda E Sanders

Thomas P Stricker

Ganesh Raj

Kevin M Dean

Reto Fiolka

Lewis C Cantley

Ariella B Hanker

Carlos L Arteaga

Affiliations

Soon will be listed here.

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.

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