title: The Cdc42/Rac1 regulator CdGAP is a novel E-cadherin transcriptional co-repressor with Zeb2 in breast cancer.
abstract: The loss of E-cadherin causes dysfunction of the cell-cell junction machinery, which is an initial step in epithelial-to-mesenchymal transition (EMT), facilitating cancer cell invasion and the formation of metastases. A set of transcriptional repressors of E-cadherin (CDH1) gene expression, including Snail1, Snail2 and Zeb2 mediate E-cadherin downregulation in breast cancer. However, the molecular mechanisms underlying the control of E-cadherin expression in breast cancer progression remain largely unknown. Here, by using global gene expression approaches, we uncover a novel function for Cdc42 GTPase-activating protein (CdGAP) in the regulation of expression of genes involved in EMT. We found that CdGAP used its proline-rich domain to form a functional complex with Zeb2 to mediate the repression of E-cadherin expression in ErbB2-transformed breast cancer cells. Conversely, knockdown of CdGAP expression led to a decrease of the transcriptional repressors Snail1 and Zeb2, and this correlated with an increase in E-cadherin levels, restoration of cell-cell junctions, and epithelial-like morphological changes. In vivo, loss of CdGAP in ErbB2-transformed breast cancer cells impaired tumor growth and suppressed metastasis to lungs. Finally, CdGAP was highly expressed in basal-type breast cancer cells, and its strong expression correlated with poor prognosis in breast cancer patients. Together, these data support a previously unknown nuclear function for CdGAP where it cooperates in a GAP-independent manner with transcriptional repressors to function as a critical modulator of breast cancer through repression of E-cadherin transcription. Targeting Zeb2-CdGAP interactions may represent novel therapeutic opportunities for breast cancer treatment.
authors.affiliation: Cancer Research Program, Research Institute of the McGill University Health Center, Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: He
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: J J
authors.initials: JJ
authors.lastname: Northey
authors.affiliation: Institut de recherches cliniques de Montréal, Montreal, Quebec, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Pelletier
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Kos
authors.affiliation: Centre de recherche du Centre Hospitalier de l'Université de Montréal (CR/CHUM), Montreal, Quebec, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Meunier
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Haibe-Kains
authors.affiliation: Centre de recherche du Centre Hospitalier de l'Université de Montréal (CR/CHUM), Montreal, Quebec, Canada.
authors.forename: A-M
authors.initials: AM
authors.lastname: Mes-Masson
authors.affiliation: Institut de recherches cliniques de Montréal, Montreal, Quebec, Canada.
authors.forename: J-F
authors.initials: JF
authors.lastname: Côté
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: P M
authors.initials: PM
authors.lastname: Siegel
authors.affiliation: Cancer Research Program, Research Institute of the McGill University Health Center, Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Lamarche-Vane
mesh_terms: D000818:Animals; D015703:Antigens, CD; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007365:Intercellular Junctions; D061986:MCF-7 Cells; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: C514543:ARHGAP31 protein, human; D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins; D020690:GTPase-Activating Proteins; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2