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

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Listed:
  • 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
    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
    Vanderbilt University Medical Center)

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.

Suggested Citation

  • 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. Strick, 2020. "Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19291-x
    DOI: 10.1038/s41467-020-19291-x
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