Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

Characterisation of isoform-specific progesterone receptor DNA binding patterns in normal and malignant breast (#94)

Dinny Graham 1 , Audrey Silvestri 1 , Tram B Doan 1 , Britta M Jacobsen 2 , Kathryn B Horwitz 2 3 , Christine L Clarke 1
  1. Westmead Institute for Cancer Research, Sydney Medical School - Westmead, University of Sydney at Westmead Millennium Institute, Westmead, NSW, Australia
  2. Department of Pathology, University of Colorado Denver, Aurora, Colorado, USA
  3. Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA

Progesterone is essential for normal development and function in the female breast. It is also implicated in breast cancer development since women exposed to progesterone analogues in hormone replacement therapy are at increased risk of developing the disease. Progesterone exerts its effects via its two nuclear receptors PRA and PRB. In the presence of ligand PR dimerises and binds DNA to regulate transcription of gene targets. PR forms both homodimers and heterodimers and all three dimer species are transcriptionally active. PRA and PRB have distinct transcriptional activities in vitro and play different tissue-specific roles. They are equivalently expressed in normal epithelial cells; however over-expression of one isoform, most often PRA, is common in breast cancer, suggesting that altered isoform expression may underlie an aberrant transcriptional response to progestins in malignancy. We previously reported in cells expressing both PR isoforms that transcriptional partners FOXA1, AP-1 and NF1, co-operate with PR to determine cell type specific genomic binding. We used PR ChIP-seq, in breast cancer cells expressing just one PR isoform, to define the factors influencing PR homodimer interactions. Both homodimers recognized a conserved progesterone response element (PRE), similar to the element bound by the heterodimer. PRB bound with higher frequency and specificity to these sites than PRA. Transcriptional cofactor motifs were detected in some binding sites, including weak enrichment of FOXA1 motifs with both homodimers, but with much lower significance than PREs, suggesting that homodimer binding is less dependent on cofactor availability in breast cancer cells. Our data suggest that in breast cancers, when PR homodimers become predominant, the specificity of progesterone regulation may be lost or reduced, resulting in inappropriate activation of deleterious signalling pathways.