title: PtdIns(3,4,5)P3-dependent Rac Exchanger 1 (PREX1) Rac-Guanine Nucleotide Exchange Factor (GEF) Activity Promotes Breast Cancer Cell Proliferation and Tumor Growth via Activation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Signaling.
abstract: PtdIns(3,4,5)P3-dependent Rac exchanger 1 (PREX1) is a Rac-guanine nucleotide exchange factor (GEF) overexpressed in a significant proportion of human breast cancers that integrates signals from upstream ErbB2/3 and CXCR4 membrane surface receptors. However, the PREX1 domains that facilitate its oncogenic activity and downstream signaling are not completely understood. We identify that ERK1/2 MAPK acts downstream of PREX1 and contributes to PREX1-mediated anchorage-independent cell growth. PREX1 overexpression increased but its shRNA knockdown decreased ERK1/2 phosphorylation in response to EGF/IGF-1 stimulation, resulting in induction of the cell cycle regulators cyclin D1 and p21(WAF1/CIP1) PREX1-mediated ERK1/2 phosphorylation, anchorage-independent cell growth, and cell migration were suppressed by inhibition of MEK1/2/ERK1/2 signaling. PREX1 overexpression reduced staurosporine-induced apoptosis whereas its shRNA knockdown promoted apoptosis in response to staurosporine or the anti-estrogen drug tamoxifen. Expression of wild-type but not GEF-inactive PREX1 increased anchorage-independent cell growth. In addition, mouse xenograft studies revealed that expression of wild-type but not GEF-dead PREX1 resulted in the formation of larger tumors that displayed increased phosphorylation of ERK1/2 but not AKT. The impaired anchorage-independent cell growth, apoptosis, and ERK1/2 signaling observed in stable PREX1 knockdown cells was restored by expression of wild-type but not GEF-dead-PREX1. Therefore, PREX1-Rac-GEF activity is critical for PREX1-dependent anchorage-independent cell growth and xenograft tumor growth and may represent a possible therapeutic target for breast cancers that exhibit PREX1 overexpression.
authors.affiliation: From the Cancer Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
authors.forename: Heng-Jia
authors.initials: HJ
authors.lastname: Liu
authors.affiliation: From the Cancer Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ooms
authors.affiliation: From the Cancer Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
authors.forename: Nuthasuda
authors.initials: N
authors.lastname: Srijakotre
authors.affiliation: From the Cancer Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
authors.forename: Joey
authors.initials: J
authors.lastname: Man
authors.affiliation: From the Cancer Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
authors.forename: Jessica
authors.initials: J
authors.lastname: Vieusseux
authors.affiliation: From the Cancer Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
authors.forename: JoAnne E
authors.initials: JE
authors.lastname: Waters
authors.affiliation: the Centenary Institute of Cancer Medicine and Cell Biology, New South Wales 2050, Australia.
authors.forename: Yue
authors.initials: Y
authors.lastname: Feng
authors.affiliation: the Centenary Institute of Cancer Medicine and Cell Biology, New South Wales 2050, Australia, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Bailey
authors.affiliation: From the Cancer Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia, Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia, and.
authors.forename: John E J
authors.initials: JE
authors.lastname: Rasko
authors.affiliation: From the Cancer Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia, the Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Victoria 8001, Australia.
authors.forename: John T
authors.initials: JT
authors.lastname: Price
authors.affiliation: From the Cancer Program, Monash Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia, christina.mitchell@monash.edu.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020662:Guanine Nucleotide Exchange Factors; C453280:PREX1 protein, human; D013629:Tamoxifen; D051057:Proto-Oncogene Proteins c-akt; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1
keywords: ERK; breast cancer; cell migration; cell proliferation; cell signaling; guanine nucleotide exchange factor (GEF)