Effects of cyclin E overexpression on cell growth and response to transforming growth factor beta depend on cell context and p27Kip1 expression.

Human tumors often display increased expression of cyclin E, suggesting that this might contribute to their abnormal growth. However, we reported recently that overexpression of a human cyclin E cDNA in the nontransformed mouse mammary epithelial cell line HC11 resulted in increased expression of the cell cycle-inhibitory protein p27Kip1 and inhibition of cell growth. To further address the role of cell context, in the present study we analyzed in parallel the effects of cyclin E overexpression in two fibroblast cell lines (Rat1 and NIH3T3) and three nontumorigenic mammary epithelial cell lines (the human cell lines 184B5 and MCF-10F and the mouse cell line HC11). This was associated with increased cyclin E-associated kinase activity in Rat1, NIH3T3, and MCF-10F cells but not in HC11 and 184B5 cells. The derivatives of the latter two cell lines showed increased expression of the p27Kip1 protein and inhibition of cell growth. There was a shortening of the G1 phase in the derivatives of the Rat1 and MCF-10F cells but not in the derivatives of the other three cell lines. Contrary to a previous hypothesis, overexpression of cyclin E was not able to confer anchorage-independent growth in any of these cell lines. However, overexpression of cyclin E was associated with increased resistance to transforming growth factor beta-mediated growth inhibition in the 184B5 and HC11 cells and a decrease in transforming growth factor beta stimulation of the Rat1 and NIH3T3 fibroblasts. Thus, overexpression of the same cyclin E cDNA has cell type-specific effects on various growth parameters. Therefore, additional studies are required to better understand the significance of the frequent increase of cyclin E expression in human tumors.