Journal
GENES & DEVELOPMENT
Volume 25, Issue 5, Pages 471-484Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1998111
Keywords
Znf703; breast cancer; metastasis; p120-catenin; E-cadherin; Wnt
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Funding
- UCSF Program for Breakthrough Biomedical Research
- National Cancer Institute [CA057621, CA129523, CA129523S1]
- Human Frontiers Science Program [RG 0051/1999-M]
- Stand up to Cancer-American Association [SU2C-AACR-DT0409]
- Wellcome Trust
- California Breast Cancer Research Program
- Medical Scientist Training Program
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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 TGF beta 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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