Progesterone: the ultimate endometrial tumor suppressor

Abstract

The uterine endometrium is exquisitely sensitive to steroid hormones that act through well-described nuclear receptors. Estrogen drives epithelial proliferation, and progesterone inhibits growth and causes cell differentiation. The importance of progesterone as a key inhibitor of carcinogenesis is reflected by the observation that women who ovulate and produce progesterone almost never get endometrial cancer. In this review we describe seminal research findings that define progesterone as the major endometrial tumor suppressor. We discuss the genes and diverse signaling pathways that are controlled by progesterone through progesterone receptors (PRs) and also the multiple factors that regulate progesterone/PR activity. By defining these progesterone-regulated factors and pathways we identify the principal therapeutic opportunities to control the growth of endometrial cancer.

Figure 1

Progesterone receptor structural elements. Diagrammed are the two primary human isoforms of progesterone receptor, PRA and PRB. PRB contains an extra 164 amino acids at the N-terminus. Within this region is AF-3, which is unique to PRB. AF, activation function; DBD, DNA-binding domain; LBD, ligand-binding domain.

Figure 2

Progesterone web of influence. Through genomic and non-genomic regulation, progesterone acts as a tumor suppressor to promote (➞) apoptosis, differentiation, and cell cycle arrest, and to inhibit ( ) inflammation and invasion.