Hormonal regulation of growth in human endometrial adenocarcinomas. Role of the p53 gene

Abstract

Oestrogen is known to have mitogenic effects on human endometrial carcinomas resulting in an increase in tumour volume. In some cases an inhibition of growth has been observed but the mechanism behind this response is not clear. In the present studies an endometrial adenocarcinoma cell line was established in vivo in nude mice and subsequently in vitro. The in vivo tumour expressed wild-type p53 while the gene had mutated in the in vitro cell line. Both the in vivo and in vitro cell line responded to oestrogen by growth inhibition but with different effects on cell kinetics. In vivo, proliferation was unaffected. Instead the cell loss factor increased and histologically the tumours were more differentiated and showed an increased number of cells undergoing apoptosis. In vitro, oestradiol induced a dose-dependent growth retardation, mediated through an accumulation of cells in G1. A parallel increase in p21 suggested that oestradiol induced a p53 independent pathway delaying cells in G1. Extending the oestradiol-treatment to six months caused increased growth re-tardation and G1 delay and added a decrease in bcl-2 expression proposing in-creased apoptosis in this subline.The effect of tamoxifen on tumour growth was studied in vivo using the wild-type p53 tumour. The effect was similar to when the tumours were influenced by oestradiol, thus, tumour growth was inhibited without affecting proliferation. Instead, the cell loss factor and p53 expression increased while the bcl-2 protein was down-regulated. Tamoxifen treatment in the in vitro cell line expressing mutant p53 caused growth retardation mainly through an increase in the DNA-synthesis time. Pretreatment with oestradiol sensitised the cells to tamoxifen, observed as increased growth inhibition.Comparing basal cell proliferation in vivo in the p53 wild-type tumour and retransplants of the mutated cell line showed higher proliferation in tumours with mutant p53 and reduced fraction of cells in G1, proposing an active suppressive function of the wild-type p53 protein in the tumours.These studies confirm the existence of the oestradiol-independent but responsive (inhibited) growth phenotype and clarify some of the intracellular mechanisms directing it.