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

Kyung-Min Lee,Carlos L Arteaga,Melinda E Sanders,Kevin M Dean,Reto Fiolka,Ganesh Raj,Alberto Servetto,Chang-Ching Lin,Angel L Guerrero-Zotano,Dhivya R Sudhan,Valerie M Jansen,Luigi Formisano,Paula González-Ericsson,Thomas P Stricker,Ariella B Hanker,Lewis C Cantley

doi:10.1038/s41467-020-19291-x

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.

Highlights

The 17q23 amplicon is associated with poor outcome in estrogen receptor (ER)+ breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear
In order to identify genes associated with poor outcome of ER+ berast cancers treated with antiestrogens, we had performed whole transcriptome analysis on RNA extracted from 58 ER+ breast cancers from patients treated with long-term letrozole for a median of 7.2 months (Supplementary Table 1; cohort of Guerrero-Zotano et al.17)
In the Kaplan–Meier Plotter database[21], high PRR11 mRNA levels were associated with a shorter relapse-free survival (RFS) of ER +/HER2− breast cancers treated with endocrine therapy (HR = 3.85; 95% confidence interval (CI), 1.95–7.59; Fig. 1d), but this association was not present in patients with HER2+ or triple-negative breast cancer (TNBC; Supplementary Fig. 1a)

Summary

Introduction

The 17q23 amplicon is associated with poor outcome in ER+ breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. 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. Preclinical and clinical studies have suggested a critical role for hyperactivation of the phosphoinositide 3-kinase (PI3K)/AKT pathway in endocrine resistance[9,10,11,12] In line with this causal role, the PI3Kα inhibitor alpelisib in combination with the ER antagonist fulvestrant was clearly superior than fulvestrant alone in patients with advanced ER+/PIK3CA mutant breast cancer[13], leading to the approval of alpelisib + fulvestrant in this subgroup of ER+ breast cancers. We performed whole transcriptome analysis on RNA extracted from 58 ER+ breast cancers from patients treated with prolonged neoadjuvant letrozole[17] In this cohort, we identified PRR11 (Proline rich 11), a protein-coding gene located in chromosome 17q22-23, to be overexpressed in tumors resistant to estrogen suppression compared to letrozole-sensitive tumors

Methods

Results

Conclusion