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Cell Growth & Differentiation Vol. 11, 335-342, June 2000
© 2000 American Association for Cancer Research

The Role of p21 in Interferon {gamma}-mediated Growth Inhibition of Human Breast Cancer Cells1

Jennifer L. Gooch, Rafael E. Herrera and Douglas Yee2

Department of Medicine/Division of Oncology, University of Texas Health Science Center, San Antonio, Texas 78284-7884

IFN-{gamma}-mediated growth inhibition requires signal transducers and activators of transcription (STAT)-1 activation and may require induction of the cyclin-dependent kinase inhibitor p21. Using an electrophoretic mobility shift assay, we identified STAT1 activation after IFN-{gamma} treatment in breast cancer cell lines. Accordingly, IFN-{gamma} inhibited proliferation of monolayer cultured MCF-7 and MDA-MB-231 breast cancer cells. Interestingly, IFN-{gamma} inhibited anchorage-independent growth of MCF-7 cells but had no effect on MDA-MB-231colony formation. Because p21 has been shown to play a role in anchorage-independent growth and is a transcriptional target of STAT1, we examined the effect of IFN-{gamma} on p21 mRNA. We found that IFN-{gamma} induced p21 mRNA in MCF-7 cells but not in MDA-MB-231 cells. Furthermore, IFN-{gamma} induced activation of a p21 promoter-luciferase reporter construct that contained the STAT1-inducible element in MCF-7 cells, but not in MDA-MB-231 cells. IFN-{gamma} treatment resulted in increased p21 protein in MCF-7 cells, whereas MDA-MB-231 cells did not appear to express detectable p21, even after IFN-{gamma} treatment. However, in MDA-MB-231 cells, p21 protein was detected only after proteosome inhibition, suggesting that degradation may be responsible for the undetectable level of p21 in these cells, despite the abundant mRNA levels. Finally, focus formation of MDA-MB-231 cells was inhibited by overexpression of p21. In conclusion, STAT1 activation does not appear to be sufficient for IFN-{gamma}-mediated growth inhibition. Furthermore, the role of p21 appears to be complex because monolayer growth inhibition occurs in the absence of p21, but anchorage-independent growth inhibition may require p21. Breast cancer cells may provide a unique model for further study of IFN-{gamma} signaling.




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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 2000 by the American Association of Cancer Research.