Figure 8.
Diverse actions of progesterone. Estradiol (E2) action via stromal ERα is critical for the development of endometrial cancer. By the same token, E2-ERα-dependent stimulation of stromal PR expression is the key protective mechanism against E2-induced carcinogenesis. Progesterone (P4) acts via stromal PR to oppose this carcinogenic effect of E2. Deficient P4 synthesis or defective stromal cell function may play key roles in the development of endometrial cancer. Interestingly, there is a progressive decline in stromal cell numbers from premalignant endometrial hyperplasia to high grade cancer, which is completely devoid of any stromal cells. In endometriosis, stromal cells are deficient in ERα but rich in ERβ. ERβ suppresses PR expression. In endometriosis, levels of PR are dramatically lower and response to P4 is blunted, resulting in promotion of survival and deficient epithelial differentiation. In breast cancer and uterine leiomyomas (fibroids), P4 acts directly via PR in malignant epithelial cells or leiomyoma smooth muscle cells with little evidence of specifically organized stromal components that mediate P4 action. In both tissues, P4 and PR are tumorigenic. In uterine leiomyoma smooth muscle cells, the primary role of E2 is to maintain PR expression.