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

Abstract

The ovarian steroid hormone, progesterone, and its nuclear receptor, the progesterone receptor, are implicated in the progression of breast cancer. Clinical trial data on the effects of hormone replacement therapy underscore the importance of understanding how progestins influence breast cancer growth. The progesterone receptor regulation of distinct target genes is mediated by complex interactions between the progesterone receptor and other regulatory factors that determine the context-dependent transcriptional action of the progesterone receptor. These interactions often lead to post-translational modifications to the progesterone receptor that can dramatically alter receptor function, both in the normal mammary gland and in breast cancer. This review highlights the molecular components that regulate progesterone receptor transcriptional action and describes how a better understanding of the complex interactions between the progesterone receptor and other regulatory factors may be critical to enhancing the clinical efficacy of anti-progestins for use in the treatment of breast cancer.

Figure 1

Schematic of progesterone receptor structure and select phosphorylation sites. Progesterone receptor (PR) isoforms A and B differ in their inclusion of an N-terminal upstream segment unique to PR-B. Both isoforms contain an identical DNA binding domain (DBD), hinge region (H) and hormone binding domain (HBD). Full-length PR-B contains 14 phosphorylation sites; serines 81, 294, 345 and 400 have known links to PR action and gene expression in breast cancer.

Figure 2

Molecular determinants of progesterone receptor action. Co-activators/repressors: interactions between PR and known transcriptional co-activators (for example, SRC1) and co-repressors (for example, NCOR/SMRT) are a key determinant of promoter specificity. Pioneer factors: interactions with predicted PR pioneer factors (for example, STAT5, putatively) lead to chromatin remodeling, allowing for efficient PR recruitment and subsequent target-gene transcription. Different pioneer factors would be predicted to determine differential PR recruitment. Post-translational modifications: phosphorylation (P), acetylation (Ac), ubiquitination (Ub), and SUMOylation (Sumo) primarily on N-terminal serine and lysine residues dictate receptor localization, turnover, subcellular localization, and promoter selectivity. Steroid receptor (SR) interactions: emerging evidence suggests that interactions between members of the steroid receptor superfamily (such as ER and PR) determine PR target-gene specificity. Scaffolding interactions: PR interaction with proteins acting as scaffolds (such as DUSP6) determine receptor post-translational modifications, thereby contributing to promoter selection. Cell cycle: phosphorylation on select PR serine residues and cell cycle-dependent protein complex formation determine receptor function and recruitment of PR to specific target genes.