Endocrine Abstracts

Studies into estrogen receptor alpha (ERα), progesterone receptor (PGR) and the androgen receptor (AR) involvement in breast, uterine and prostate cancers has provided considerable insight into the molecular actions these receptors, but have thus far focused on each receptor individually and alone in different cell types. Here, whole genome expression microarray analysis and ChIP-sequencing in ZR-75-1 breast cancer cells, in response to combinations of 17β-estradiol (E2), progesterone (PROG) and 5α-dihydrotestosterone (DHT), was used to provide new information on action of steroid combinations. For each steroid/receptor alone, a remarkably small subset of high affinity binding sites and expression responses were found to be common amongst different cells and disease states (<10%). The larger proportion of lower affinity sites and responses were found to predominate, and likely govern cell specificity of hormone responses. Importantly, when we add more than one hormone, we identify distinct DNA binding patterns for each receptor, as well as unique gene expression profiles and important gene families critical in cellular function. For example, long term E2 treatment in combination with PROG results in a dramatic 10-fold increase in the number of PGR binding sites detected at an equivalent peak threshold in comparison to PROG alone. Furthermore, only E2 and PROG combination treatment resulted in PGR binding sequences enriched for hormone response elements and important coregulator binding sequences, such as FOXA1. These data suggest that the actions of steroid receptors in breast cancer cells are not additive or independent, but combine in a different way to produce a unique cellular response that is not evident by investigation of each receptor in isolation.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details unavailable.