INCREASED EXPRESSION OF CYCLIN D1 IN A MURINE MAMMARY EPITHELIAL-CELLLINE INDUCES P27(KIP1), INHIBITS GROWTH, AND ENHANCES APOPTOSIS

Cyclin D1 is frequently amplified and/or overexpressed in human breast cancer and several other types of cancer. To examine the role of cycl in D1 in normal mammary epithelial cells, in the present study we have overexpressed human cyclin D1 in the mouse mammary epithelial cell li ne HC11, using retrovirus-mediated transduction. We found that the cyc lin D1 overexpresser clones displayed a decrease in saturation density , a decrease in anchorage-independent growth, an increased fraction of cells in the G(0)-G(1) phase, and increased expression of beta-casein , when compared to the control cells, The latter finding suggested tha t they were more differentiated. Furthermore, the cyclin D1 overexpres sers displayed a marked increase in susceptibility to induction of apo ptosis by serum withdrawal or by treatment with hydroxyurea or the pro tein kinase C inhibitors CGP 41251 and Ro31-8220. Thus, in some mammar y epithelial cells, increased expression of cyclin D1 can inhibit grow th, induce differentiation, and enhance apoptosis. These effects might be due, at least in part, to the fact that these derivatives displaye d increased expression of the p27(kip1) inhibitory protein.