Remodelling the genomic landscape: nuclear cofactors and DNA structure influence progesterone response in normal breast and breast cancer (#4)
The ovarian hormone progesterone plays a key role in regulating a diverse range of female reproductive functions, which include development of lobular alveolar structures of the breast, decidualization of the endometrium, maintenance of bone density and regulation of inflammatory and immune functions. Large randomized trials of exposure to progesterone analogues in hormone replacement therapy have established its role in increasing breast cancer risk, yet the mechanisms that confine this adverse influence to the breast, and likely underlie its diverse tissue specificity, are incompletely understood. Progesterone effects are mediated via the nuclear progesterone receptor (PR), which binds to specific sequences in genomic DNA to regulate transcription of target genes. Ligand activation of PR results in nuclear repositioning into transcriptional hotspots, which are dependent on PR interactions with both the nuclear matrix and chromatin for their fidelity. In the disrupted nuclear environment of breast cancer, aberrant PR nuclear localisation is observed, and results in an altered PR-regulated transcriptional programme compared to non-malignant breast. We reasoned that such cell specificity in response to progesterone may be reflected in differing patterns of PR genomic interaction, which we began to explore by mapping PR genomic interactions in breast cancer and minimally transformed normal breast cells. There were striking differences in PR genomic interactions in these two cell types, which was reflected in largely non-overlapping progesterone regulated transcriptomes. Motif analysis of PR binding sites suggested that while PR binds to similar response elements in the two cell types, the cofactors that direct PR binding by facilitating chromatin accessibility are quite different.