Finally! A Model for Progesterone Receptor Action in Normal Human Breast

Abstract

Substantial clinical and experimental data over the years have supported the conclusion that estradiol-17β is the ovarian hormone primarily responsible for growth and progression of breast cancer (1). Progesterone was assumed to have negligible effects on breast tumorigenesis, in part because of its well established role to inhibit the proliferative effect of estrogen in the epithelial compartments of the endometrium and promote differentiation of the uterine glands (2). However, much publicized observational and clinical studies have more recently implicated progesterone as a proliferative hormone in the normal human breast and as a life-long risk factor for breast cancer, suggesting progesterone also contributes to early stages of breast tumorigenesis (3,4,5,6,7,8,9). Paradoxically, in established breast cancers, the presence of progesterone receptor (PR) in the primary tumor is an independent marker of favorable prognosis and is associated with a more differentiated tumor phenotype, suggesting progesterone has a protective role against progression and invasion once a tumor has developed (10,11,12). Indeed, in most PR-positive breast cancer cell lines, progestins induce a transient proliferation followed by cell cycle arrest such that the long-term effect is growth inhibition (13). This apparent dichotomy suggests that progesterone signaling is altered during disease progression. Uncertainties concerning the role of progesterone in the normal human breast and tumorigenesis have been due in part to the absence of a suitable PR-positive progesterone-responsive experimental system for the normal human breast.