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Role of the Cyclin-Dependent Kinase Inhibitor p27^Kip1 in Androgen-Induced Inhibition of CAMA-1 Breast Cancer Cell Proliferation

Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Laval University, Québec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Dr. Claude Labrie, Oncology and Molecular Endocrinology Research Center, CHUL Research Center, 2705 Laurier Boulevard, Québec, Québec, Canada G1V 4G2. E-mail: claude.labrie{at}crchul.ulaval.ca

Androgens are known to inhibit the growth of breast cancer cells, but the molecular mechanism of androgen-induced growth inhibition remains unknown. To address this question, we examined functional and quantitative alterations in cell cycle regulators in the E-responsive CAMA-1 breast cancer cell line. We report here that the androgen 5-dihydrotestosterone inhibits the proliferation of CAMA-1 breast cancer cells. This inhibition of cell proliferation was dose dependent, and maximal inhibition of E2-stimulated proliferation was observed at the concentration of 1 nM 5-dihydrotestosterone. 5-Dihydrotestosterone-induced growth arrest was accompanied by an increase in the proportion of cells in the G₁ phase of the cell cycle. Compared with control cells, 5-dihydrotestosterone-treated cells showed an increase in the relative proportion of hypophosphorylated retinoblastoma protein consistent with G₁ arrest. In CAMA-1 cells, 5-dihydrotestosterone caused an accumulation of the cyclin-dependent kinase inhibitor p27^Kip1. Cyclin E-cyclin-dependent kinase-2-associated kinase activity was strongly inhibited in 5-dihydrotestosterone-treated cells, and immunoprecipitation-Western blot analysis showed an increase in the amount of p27^Kip1 associated with cyclin E-cyclin-dependent kinase-2 complexes. These results suggest that inhibition of breast cancer cell growth by androgens may be mediated at least in part by inactivation of the cyclin E-cyclin-dependent kinase-2 complexes by p27^Kip1.

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