Progesterone regulation of activating protein-1 transcriptional activity: a possible mechanism of progesterone inhibition of endometrial cancer cell growth

The uterine endometrium and cancers derived from it are classic models of hormone action: estrogen promotes growth and progesterone inhibits proliferation and results in differentiation. We have now identified a major pathway through which progesterone causes these growth-limiting effects. Ligand-bound progesterone receptors modulate the composition and transcriptional activity of members of the activating protein-1 (AP-1) family, and in particular, c-Jun. First, a dominant negative form of c-Jun inhibits the constitutive growth of Hec50co cells in a manner similar to the effects of progesterone through progesterone B receptors. Second, progesterone inhibits the transcriptional activity of the AP-1 complex in reporter gene assays. Third, the DNA binding of AP-1 and the composition of the individual AP-1 factors on DNA is regulated by progesterone on electrophoretic mobility shift assays. Fourth, progesterone strongly inhibits total AP-1 as well as c-Jun recruitment to the cyclin D1 promoter, but enhances AP-1 occupancy on the p53 and p21 promoters, as shown by chromatin immunoprecipitation assays. The effects of progesterone on AP-1 DNA binding are confirmed to result in altered transcription of these AP-1 target genes by RT-PCR. These studies establish that modulation of AP-1 activity is a potential pathway of progesterone-induced growth inhibition in endometrial cancer cells.