Zeppo1 is a novel metastasis promoter that represses E-cadherin expression and regulates p120-catenin isoform expression and localization
- 1Department of Anatomy, University of California at San Francisco, San Francisco, California 94143-0452, USA;
- 2Biomedical Sciences Program, University of California at San Francisco, San Francisco, California 94143-0452, USA
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.
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Footnotes
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↵3 Corresponding author.
E-MAIL zena.werb{at}ucsf.edu; FAX (415) 476-4565.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1998111.
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Supplemental material is available for this article.
- Received September 30, 2010.
- Accepted January 18, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press