LB55

Oestrogen receptor interactions with the coactivator AIB1 in development of resistance to aromatase inhibitor treatment for breast cancer

Jane O'Hara, Marie McIlroy, Arnold Hill, Leonie Young

Royal College of Surgeons Ireland, Dublin, Ireland

Aromatase inhibitors are fast becoming the first line treatment for post menopausal breast cancer patients. It is evident however, that aromatase inhibitors do not remove all ligand, in vitro data from molecular studies suggest that this can result in adaptive oestrogen hypersensitivity of the oestrogen receptor (ER) with consequent resistance. We hypothesised therefore that, in the endocrine resistant setting, ER may have the capacity to recruit its coactivator protein AIB1 to drive transcription of ER sensitive genes.

To investigate the molecular mechanisms of aromatase inhibitor (AI) resistance we have generated a breast cancer cell line over-expressing the aromatase enzyme, resistant to the AI letrozole (MCF7aroR-Let). In these cells, increased proliferation and ER target gene expression in the presence of both the aromatase substrate, androstenedione, and letrozole was observed, compared with MCF-7 cells overexpressing aromatase (MCF-7aro). Moreover, chromatin immunoprecipitation studies were used to demonstrate recruitment of both ERalpha and AIB1 to the promoter of classic (pS2) and non-classic (c-myc and cyclinD1) ER target genes in MCF7aroR-Let, with letrozole treatment.

These data suggest that in the endocrine resistant setting ERalpha can utilise AIB1 to drive tumour progression in the presence of an AI. This study provides an opportunity to understand the mechanisms of aromatase inhibitor resistance before it becomes a significant clinical problem.