Progesterone receptor genomic and transcriptomic effects are shaped by estrogen priming to produce a unique response in breast cancer cells

Introduction: Progesterone receptor (PR) is essential for normal breast homeostatic maintenance and is important for dynamic breast remodelling through the menstrual cycle and pregnancy. Furthermore, it is now clear that PR plays a mitogenic role in breast cancer. However, current studies investigating the cellular mechanisms of action of this estrogen-regulated gene fail to consider its activity in the context of estrogen (E2). Methods: In this study we contrast the transcriptomic and genomic function of PR in estrogen primed breast cancer cells using microarray and chromatin immunoprecipitation-sequencing (ChIP-seq) with the function of PR in two non-estrogen primed breast cancer cell lines. Results: We find a dramatic increase in the number of genes regulated by PR in estrogen primed cells, resulting in a transcriptomic response that is unique in comparison to the response in non-estrogen primed cells. Furthermore, we report that estrogen priming leads to a 10 fold increase in the number of PR binding events to the genome, and we describe direct regulation of Epithelial Growth Factor Receptor (EGFR) and growth factor receptor pathways by P4 in the context of E2 treatment. Conclusion: These results show that PR is important for modulating both the E2 and growth factor signalling pathways, thereby shaping the overall cellular response and intrinsic subtype in breast cancer cells.