Role of the cyclin-dependent kinase inhibitor p27(Kip1) in androgen-induced inhibition of CAMA-1 breast cancer cell proliferation.
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 alpha-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 alpha-dihydrotestosterone. 5 alpha-Dihydrotestosterone-induced growth arrest was accompanied by an increase in the proportion of cells in the G(1) phase of the cell cycle. Compared with control cells, 5 alpha-dihydrotestosterone-treated cells showed an increase in the relative proportion of hypophosphorylated retinoblastoma protein consistent with G(1) arrest. In CAMA-1 cells, 5 alpha-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 alpha-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).
Lapointe
J
J
Oncology and Molecular Endocrinology Research Center, CHUL Research Center and Laval University, Québec, Canada G1V 4G2.
Labrie
C
C
D000728:Androgens / Q000494:pharmacology* / Q000502:physiology; D001943:Breast Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D018797:Cell Cycle Proteins / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D006801:Humans; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D000728:Androgens; D018797:Cell Cycle Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27