P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT and MEK/ERK signaling in breast cancer

L. M. Dillon, J. R. Bean, W. Yang, K. Shee, L. K. Symonds, J. M. Balko, W. H. McDonald, S. Liu, A. M. Gonzalez-Angulo, G. B. Mills, C. L. Arteaga, T. W. Miller

    Research output: Contribution to journalArticlepeer-review

    45 Scopus citations

    Abstract

    Phosphatidylinositol 3-kinase (PI3K) promotes cancer cell survival, migration, growth and proliferation by generating phosphatidylinositol 3,4,5-trisphosphate (PIP 3) in the inner leaflet of the plasma membrane. PIP 3 recruits pleckstrin homology domain-containing proteins to the membrane to activate oncogenic signaling cascades. Anticancer therapeutics targeting the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway are in clinical development. In a mass spectrometric screen to identify PIP 3 -regulated proteins in breast cancer cells, levels of the Rac activator PIP 3 -dependent Rac exchange factor-1 (P-REX1) increased in response to PI3K inhibition, and decreased upon loss of the PI3K antagonist phosphatase and tensin homolog (PTEN). P-REX1 mRNA and protein levels were positively correlated with ER expression, and inversely correlated with PI3K pathway activation in breast tumors as assessed by gene expression and phosphoproteomic analyses. P-REX1 increased activation of Rac1, PI3K/AKT and MEK/ERK signaling in a PTEN-independent manner, and promoted cell and tumor viability. Loss of P-REX1 or inhibition of Rac suppressed PI3K/AKT and MEK/ERK, and decreased viability. P-REX1 also promoted insulin-like growth factor-1 receptor activation, suggesting that P-REX1 provides positive feedback to activators upstream of PI3K. In support of a model where PIP 3 -driven P-REX1 promotes both PI3K/AKT and MEK/ERK signaling, high levels of P-REX1 mRNA (but not phospho-AKT or a transcriptomic signature of PI3K activation) were predictive of sensitivity to PI3K inhibitors among breast cancer cell lines. P-REX1 expression was highest in estrogen receptor-positive breast tumors compared with many other cancer subtypes, suggesting that neutralizing the P-REX1/Rac axis may provide a novel therapeutic approach to selectively abrogate oncogenic signaling in breast cancer cells.

    Original languageEnglish (US)
    Pages (from-to)3968-3976
    Number of pages9
    JournalOncogene
    Volume34
    Issue number30
    DOIs
    StatePublished - Jul 23 2015

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

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