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Protein Kinase C ß Enhances Growth and Expression of Cyclin D1 in Human Breast Cancer Cells

¹ Herbert Irving Comprehensive Cancer Center, ² Department of Medicine, and ³ Institute of Human Nutrition, Columbia University, New York, New York

Requests for reprints: I. Bernard Weinstein, Herbert Irving Comprehensive Cancer Center, Columbia University, 701 West 168th Street, New York, NY 10032. Phone: 212-305-6921; Fax: 212-305-6889; E-mail: ibw1{at}columbia.edu.

Although alterations in the expressions of protein kinase C (PKC) have been implicated in breast carcinogenesis, the roles of specific isoforms in this process remain elusive. In the present study, we examined the specific roles of PKCß1 and ß2 in growth control in human breast cancer cell lines. The PKCß-specific inhibitor LY379196 significantly inhibited growth of the breast cancer cell lines MCF-7, MDA-MB-231, and BT474, but not the normal mammary epithelial cell line MCF-10F. Treatment of MCF-7 cells with LY379196 caused an increase in the fraction of cells in the G₁ phase of the cell cycle. To explore the roles of PKCß1 and ß2, we used cDNA expression vectors that encode wild-type and constitutively activated or dominant negative mutants of these two proteins. When compared with vector controls, derivatives of MCF-7 cells that stably overexpress wild-type PKCß1 or PKCß2 displayed a slight increase in growth rate; derivatives that stably express the constitutively active mutants of PKCß1 or PKCß2 displayed a marked increase in growth rate; and derivatives that stably express a dominant negative mutant of PKCß1 or ß2 displayed inhibition of growth. The derivatives of MCF-7 cells that stably express the constitutively activated mutants of PKCß1 or ß2 were more resistant to growth inhibition by LY379196 than the vector control MCF-7 cells. Immunoblot analysis indicated that MCF-7 cells that stably overexpress wild-type or constitutively activated mutants of PKCß1 or ß2 had higher cellular levels of cyclin D1 than vector control cells, whereas cells that express a dominant negative mutant had decreased levels of cyclin D1. The derivatives that stably express the constitutively activated mutants of PKCß1 or ß2 also displayed increased cyclin D1 promoter activity in transient transfection luciferase reporter assays, and this induction of activity requires activator protein 1. Constitutively activated PKCß1 and ß2 also enhanced the transcription of c-fos in transient transfection luciferase reporter assays. Thus, PKCß1 and ß2 may play important positive roles in the growth of at least a subset of human breast cancers. Therefore, inhibitors of these isoforms may be useful in breast cancer chemoprevention or therapy. (Cancer Res 2006; 66(23): 11399-408)

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