Chapter 4 Progestin regulation of cellular proliferation

Abstract

Progestins have diverse effects on cell proliferation in progestin target tissues which are developmentally regulated as well as being species- and cell type-specific. Both stimulatory and inhibitory effects are well documented but it is still unclear whether the stimulatory effects are sustained, i.e., whether they result in continued rounds of cell replication or result in transient effects on a given cell population, inducing a single round of replication before cells undergo terminal differentiation. The inhibitory effects have been more clearly defined, particularly for endometrial epithelium in vivo and for both endometrial and breast carcinoma cells in vitro. Progestin-induced inhibition of cell proliferation results from a block in cell cycle progression in early G1 phase immediately after mitosis indicating that progestins inhibit the production and/or functions of genes critical to progression through early G1 phase. These genes have not been identified but candidates include the proto-oncogene c-myc and the G1 cyclins, particularly cyclin D1 and its kinase partners. Recent studies employing human mammary carcinoma cells as models have documented a progestin-induced stimulation of cell cycle progression in G1 phase. This effect appears to be confined to cells that are already in G1 phase and leads to accelerated progression through this phase of the cell cycle. Since other phases appear unaffected, the resultant effect is a significantly reduced cell generation time, i.e., an increased rate of cell proliferation. Whether or not this is a good model for the stimulatory effects of progestins in vivo remains to be established. Studies of changes in gene expression accompanying increased G1 transit have demonstrated that this effect is preceded by induction of c-myc and cyclin D1. Since delayed administration of a progestin antagonist inhibited cell cycle progression and cyclin D1 induction and the effects of progestins were mimicked by inducible expression of a transfected cyclin D1 construct, there is strong evidence that transcriptional activation of cyclin D1 is causal for progestin stimulation of cell proliferation. These data, generated from well-characterized experimental models in vitro, have facilitated progress in our understanding of mechanisms of progestin action. The hypotheses developed from these systems urgently need to be validated in a broader spectrum of progestin target tissues including female reproductive organs in vivo. Such data are essential to an understanding of the further physiology of progestin action and the optimal use of progestins in the management of human disease.