Unraveling the human progesterone receptor signal transduction pathway Insights into antiprogestin action

The steroid hormone progesterone is a key modulator of the cellular processes that are required for the development and maintenance of reproductive function. Produced primarily by ovarian granulosa cells, it mediates its biological activity throughout the body by interacting with specific high-affinity nuclear receptors located in target cell nuclei. These receptors are latent transcription factors, which, upon binding progesterone, are capable of interacting with specific recognition sequences within target gene promoters. The consequence of these interactions are determined by the cell and promoter context of the DNA-bound receptor. Abnormalities in the progesterone receptor (PR) signal transduction pathway are implicated in pathological states such as breast cancer, endometriosis, and uterine fibroids. Consequently, as a result of the medical need to modulate PR transcriptional activity, antiprogestins, compounds that oppose the actions of progesterone, have been developed. Recent advances in our understanding of the molecular mechanism of action of progesterone have revealed the likely mechanisms by which antiprogestins manifest their biological activity. It is anticipated that this new information will facilitate the discovery and development of additional antiprogestins that may demonstrate superior therapeutic profiles.