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 P Fiolka; Lewis C. Cantley; Ariella B. Hanker; Carlos L. Arteaga

doi:10.1038/s41467-020-19291-x

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 P Fiolka, Lewis C. Cantley, Ariella B. Hanker, Carlos L. Arteaga

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30 Scopus citations

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.

Original language	English (US)
Article number	5488
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19291-x
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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Lee, K. M., Guerrero-Zotano, A. L., Servetto, A., Sudhan, D. R., Lin, C. C., Formisano, L., Jansen, V. M., González-Ericsson, P., Sanders, M. E., Stricker, T. P., Raj, G., Dean, K. M., Fiolka, R. P., Cantley, L. C., Hanker, A. B., & Arteaga, C. L. (2020). Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer. Nature communications, 11(1), Article 5488. https://doi.org/10.1038/s41467-020-19291-x

Lee, KM, Guerrero-Zotano, AL, Servetto, A, Sudhan, DR, Lin, CC, Formisano, L, Jansen, VM, González-Ericsson, P, Sanders, ME, Stricker, TP, Raj, G , Dean, KM, Fiolka, RP, Cantley, LC, Hanker, AB & Arteaga, CL 2020, 'Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer', Nature communications, vol. 11, no. 1, 5488. https://doi.org/10.1038/s41467-020-19291-x

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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.}",

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doi = "10.1038/s41467-020-19291-x",

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AU - Lee, Kyung min

AU - Guerrero-Zotano, Angel L.

AU - Servetto, Alberto

AU - Sudhan, Dhivya R

AU - Lin, Chang Ching

AU - Formisano, Luigi

AU - Jansen, Valerie M.

AU - González-Ericsson, Paula

AU - Sanders, Melinda E.

AU - Stricker, Thomas P.

AU - Raj, Ganesh

AU - Dean, Kevin M.

AU - Fiolka, Reto P

AU - Cantley, Lewis C.

AU - Hanker, Ariella B.

AU - Arteaga, Carlos L.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

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

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