title: P-REX1 creates a positive feedback loop to activate growth factor receptor, PI3K/AKT and MEK/ERK signaling in breast cancer.
abstract: Phosphatidylinositol 3-kinase (PI3K) promotes cancer cell survival, migration, growth and proliferation by generating phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the inner leaflet of the plasma membrane. PIP3 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 PIP3-regulated proteins in breast cancer cells, levels of the Rac activator PIP3-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 PIP3-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.
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Dillon
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Bean
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Shee
authors.affiliation: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: L K
authors.initials: LK
authors.lastname: Symonds
authors.affiliation: 1] Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA [2] Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Balko
authors.affiliation: Proteomics Laboratory, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: W H
authors.initials: WH
authors.lastname: McDonald
authors.affiliation: 1] Department of Breast Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA [2] Department of Systems Biology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: 1] Department of Breast Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA [2] Department of Systems Biology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Gonzalez-Angulo
authors.affiliation: Department of Systems Biology, MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: 1] Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA [2] Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA [3] Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Arteaga
authors.affiliation: 1] Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA [2] Comprehensive Breast Cancer Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Miller
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D025461:Feedback, Physiological; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C453280:PREX1 protein, human; D017978:Receptors, Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020744:rac GTP-Binding Proteins