title: Zeppo1 is a novel metastasis promoter that represses E-cadherin expression and regulates p120-catenin isoform expression and localization.
abstract: Amplification of 8p11-12 in human breast cancers is associated with increased proliferation and tumor grade and reduced metastasis-free patient survival. We identified Zeppo1 (zinc finger elbow-related proline domain protein 1) (FLJ14299/ZNF703) within this amplicon as a regulator of cell adhesion, migration, and proliferation in mammary epithelial cells. Overexpression of Zeppo1 reduces cell-cell adhesion and stimulates migration and proliferation. Knockdown of Zeppo1 induces adhesion and lumen formation. Zeppo1 regulates transcription, complexing with Groucho and repressing E-cadherin expression and Wnt and TGFβ reporter expression. Zeppo1 promotes expression of metastasis-associated p120-catenin isoform 1 and alters p120-catenin localization upon cell contact with the extracellular matrix. Significantly, Zeppo1 overexpression in a mouse breast cancer model increases lung metastases, while reducing Zeppo1 expression reduces both tumor size and the number of lung metastases. These results indicate that Zeppo1 is a key regulator of breast cancer progression.
authors.affiliation: Department of Anatomy, University of California at San Francisco, San Francisco, California 94143-0452, USA.
authors.forename: Euan M
authors.initials: EM
authors.lastname: Slorach
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chou
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D051177:Catenins / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000235:genetics*; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000095002:Delta Catenin
chemical_list: D015820:Cadherins; D051177:Catenins; D020033:Protein Isoforms; D012097:Repressor Proteins; C557412:Zeppo1 protein, mouse; D000095002:Delta Catenin