OVEREXPRESSION OF P27(KIP1) INHIBITS THE GROWTH OF BOTH NORMAL AND TRANSFORMED HUMAN MAMMARY EPITHELIAL-CELLS

We previously reported increased expression of p27(Kip1) in a series o f human breast cancer cell lines, as compared to cell lines establishe d from normal mammary epithelial cells. These data were surprising bec ause this protein exerts a growth-inhibitory function in normal cells, and p27(Kip1) has been proposed as a candidate tumor suppressor gene, A possible explanation for the paradoxical increase in p27(Kip1) in t he breast cancer cell lines is that they had become refractory to the inhibitory effects of this protein, To address this question, here, we transfected the MCF7 breast cancer cell line and the MCF10F nontumori genic mammary epithelial cell line with a vector containing the p27(Ki p1) cDNA to obtain derivatives that express increased levels of p27(Ki p1), The increased expression of p27(Kip1) in both of these cell lines was associated with lengthening of the G(1) phase, an increase in the doubling time, a decreased saturation density, and a decreased platin g efficiency, In the MCF7 cells, anchorage-independent growth and ill who tumorigenicity were also suppressed. These effects were associated with decreased cyclin E-associated in vitro kinase activity in both c ell lines. The increased expression of p27(Kip1) was associated with a decreased level of expression of cyclin D1 in the MCF10F cells but an increased level of the cyclin D1 protein in the MCF7 cell Line. Both derivatives expressed slightly increased levels of the cyclin E protei n. Thus, breast cancer cells are still responsive to p27(Kip1)-mediate d inhibition of cell growth despite the high basal level of this prote in. These results suggest that therapeutic strategies that further inc rease the level of expression of p27(Kip1) or mimic its activity might he useful in cancer therapy.