Short- and long-term oestradiol treatment inhibits growth and alters expression of p21WAF1/Cip1 in an endometrial adenocarcinoma cell line lacking functional p53.

Oestrogen is assumed to play a significant role in cell cycle regulation of cells expressing the oestrogen receptor, although its mechanism of action is not yet well defined. To examine this, a mutant p53-expressing human endometrial adenocarcinoma cell line of the oestradiol-inhibited growth phenotype was treated with oestradiol for 2 weeks (short-term) and 6 months (long-term). With short-term treatment, cells were treated with increasing doses of oestradiol. The highest dose, 1 microM, was used in the long-term interval. The influence of the hormone on growth, proliferation and expression of some cell cycle and apoptosis-related proteins was evaluated. In cells treated for 2 weeks, there was a dose-dependent inhibition of both growth and proliferation with a significant decrease in labelling index (LI) and S-phase fraction (SPF) and a simultaneous increase in the fraction of cells in G0/G1. Extending the oestradiol treatment to 6 months showed further growth retardation and decreased proliferation with cells accumulating in G0/G1. Analysis of the expression of p21WAF1/Cip1 showed a nearly 2-fold increase after 2 weeks treatment with 1 microM oestradiol, which was also observed after long-term treatment without any further increase in protein levels. Expression of the anti-apoptotic protein bcl-2 was not affected after short-term treatment but decreased significantly after 6 months treatment compared to control cells. Our results suggest the existence of a p53-independent pathway of oestradiol regulation of growth and proliferation in this human endometrial adenocarcinoma, resulting in accumulation of cells in G0/G1 through p21WAF1/Cip1 induction and, after prolonged treatment, downregulation of bcl-2 protein.