Molecular insights of pathways resulting from two common PIK3CA mutations in breast cancer

Poornima Bhat-Nakshatri, Chirayu P. Goswami, Sunil Badve, Luca Magnani, Mathieu Lupien, Harikrishna Nakshatri

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The PI3K pathway is activated in approximately 70% of breast cancers. PIK3CA gene mutations or amplifications that affect the PI3K p110α subunit account for activation of this pathway in 20% to 40% of cases, particularly in estrogen receptor alpha (ERα)-positive breast cancers. AKT family of kinases, AKT1-3, are the downstream targets of PI3K and these kinases activate ERa. Although several inhibitors of PI3K have been developed, none has proven effective in the clinic, partly due to an incomplete understanding of the selective routing of PI3K signaling to specific AKT isoforms. Accordingly, we investigated in this study the contribution of specific AKT isoforms in connecting PI3K activation to ERα signaling, and we also assessed the utility of using the components of PI3K-AKT isoform-ERα signaling axis as predictive biomarkers of response to PI3K inhibitors. Using a variety of physiologically relevant model systems with defined natural or knock-in PIK3CA mutations and/or PI3K hyperactivation, we show that PIK3CA-E545K mutations (found in ∼20% of PIK3CA-mutant breast cancers), but not PIK3CA-H1047R mutations (found in 55% of PIK3CA-mutant breast cancers), preferentially activate AKT1. Our findings argue that AKT1 signaling is needed to respond to estrogen and PI3K inhibitors in breast cancer cells with PIK3CA-E545K mutation, but not in breast cancer cells with other PIK3CA mutations. This study offers evidence that personalizing treatment of ER-positive breast cancers to PI3K inhibitor therapy may benefit from an analysis of PIK3CA-E545K-AKT1-estrogen signaling pathways.

Original languageEnglish (US)
Pages (from-to)3989-4001
Number of pages13
JournalCancer Research
Volume76
Issue number13
DOIs
StatePublished - Jul 1 2016

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Phosphatidylinositol 3-Kinases
Breast Neoplasms
Mutation
Estrogen Receptor alpha
Protein Isoforms
Estrogens
Phosphotransferases
Biomarkers

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Molecular insights of pathways resulting from two common PIK3CA mutations in breast cancer. / Bhat-Nakshatri, Poornima; Goswami, Chirayu P.; Badve, Sunil; Magnani, Luca; Lupien, Mathieu; Nakshatri, Harikrishna.

In: Cancer Research, Vol. 76, No. 13, 01.07.2016, p. 3989-4001.

Research output: Contribution to journalArticle

Bhat-Nakshatri, Poornima ; Goswami, Chirayu P. ; Badve, Sunil ; Magnani, Luca ; Lupien, Mathieu ; Nakshatri, Harikrishna. / Molecular insights of pathways resulting from two common PIK3CA mutations in breast cancer. In: Cancer Research. 2016 ; Vol. 76, No. 13. pp. 3989-4001.
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abstract = "The PI3K pathway is activated in approximately 70{\%} of breast cancers. PIK3CA gene mutations or amplifications that affect the PI3K p110α subunit account for activation of this pathway in 20{\%} to 40{\%} of cases, particularly in estrogen receptor alpha (ERα)-positive breast cancers. AKT family of kinases, AKT1-3, are the downstream targets of PI3K and these kinases activate ERa. Although several inhibitors of PI3K have been developed, none has proven effective in the clinic, partly due to an incomplete understanding of the selective routing of PI3K signaling to specific AKT isoforms. Accordingly, we investigated in this study the contribution of specific AKT isoforms in connecting PI3K activation to ERα signaling, and we also assessed the utility of using the components of PI3K-AKT isoform-ERα signaling axis as predictive biomarkers of response to PI3K inhibitors. Using a variety of physiologically relevant model systems with defined natural or knock-in PIK3CA mutations and/or PI3K hyperactivation, we show that PIK3CA-E545K mutations (found in ∼20{\%} of PIK3CA-mutant breast cancers), but not PIK3CA-H1047R mutations (found in 55{\%} of PIK3CA-mutant breast cancers), preferentially activate AKT1. Our findings argue that AKT1 signaling is needed to respond to estrogen and PI3K inhibitors in breast cancer cells with PIK3CA-E545K mutation, but not in breast cancer cells with other PIK3CA mutations. This study offers evidence that personalizing treatment of ER-positive breast cancers to PI3K inhibitor therapy may benefit from an analysis of PIK3CA-E545K-AKT1-estrogen signaling pathways.",
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