Molecular determinants of context-dependent progesterone receptor action in breast cancer

The mitogenic activity of estrogen is well established, but an under-studied ovarian steroid hormone, progesterone, is emerging as a primary mitogen in the breast, contributing significantly to genetic programming required for mammary stem cell self-renewal, mammary gland development, proliferation, and hyperplasia [1]. The effects of progesterone are triggered after binding of progesterone to its intracellular receptor, the progesterone receptor (PR). The PR exists in two primary isoforms, differing structurally by the inclusion of an N-terminal segment unique to the full-length isoform, PR-B [2] (Figure 1). This region, termed the B-upstream segment, is missing from the shorter isoform, PR-A [3]. The two isoforms are encoded by the same gene (regulated by distinct but tandem upstream promoters) and are most often co-expressed [4]. The PR is a member of the steroid hormone receptor subgroup of ligand-activated transcription factors within the large nuclear receptor superfamily, and is an important down-stream effector of estrogen-receptor (ER) signaling; in most circumstances, estrogen is required for robust PR expression. PR binding to DNA, either directly through progesterone response elements or indirectly through tethering interactions with other transcription factors, activates transcriptional profiles associated with mammary gland proliferation and breast cancer [5-9]. Additionally, PR binding interactions with transcriptional co-activators and repressors are critical to PR transcription factor function [10].