Establishing the role of coactivator/corepressors associated with ER in LTED and TamR cells.

We believe that this study will provide further evidence for the altered role of coactivator/corepressor activity in the endocrine resistant setting.

Oestrogens exert their effects by binding to the ER resulting in hyperphosphorylation and dimerisation. E2-bound ER interacts with oestrogen response elements (ERE) within target genes leading to the recruitment of coactivators of the p160 family which associate with the transcription factor CBP facilitating histone acetylation. Differential expression of the p160 coactivators/corepressors has been implicated in the tissue selective activity of tamoxifen. More recently the impact of growth factor signalling influencing coactivator recruitment to the ER has been suggested. ERBB2 signalling pathways have been shown to differentially effect sensitivity of breast cancer cells to oestrogen deprivation and tamoxifen as a result of altered p160 coactivator/corepressor recruitment to the ER.

To establish the role of coactivator/corepressors associated with ER in the LTED and TamR cells, we are using a technology called chromatin immunoprecipitation (ChIP) and re-ChIP which allows the investigation of multiple cofactor-DNA interactions in the resistant versus the parental cells. We believe that this study will provide further evidence for the altered role of coactivator/corepressor activity in the endocrine resistant setting and provide potential targets for clinical intervention.