B50

Examining a role for histone methyltransferases and demethylases in estrogen-dependent breast cancer

Luke Gaughan, Kelly Armstrong, Lynsey Rogerson, Craig Robson

Newcastle University, UK

The importance of the estrogen receptor (ER) in breast cancer development makes it a prominent target for therapy. Current treatments, however, have limited effectiveness hence the definition of new therapeutic targets is vital. The ER is a member of the nuclear hormone receptor superfamily of transcription factors that requires co-regulator proteins for complete regulation. Aberrant activity of co-regulators has been postulated to result in failure of ER-targeted treatments.

The function of histone methyltransferases (HMTs) and demethylases (HDMs) in ER co-regulation remains largely ill-defined. The finding that the HMT EZH2 enhances ER activity and is overexpressed in breast cancer implicates a role for these enzymes in receptor regulation and tumourigenesis.

We have applied an unbiased, pre-validated siRNA library screen to identify additional HMT and HDM enzymes that regulate ER activity in breast cancer cells. Initial indications implicate several previously uncharacterised HMT and HDM enzymes are capable of regulating ER activity.

Our focus is now to further characterise the role of these selected HMT and HDM enzymes in regulating ER-mediated transcription in several models of breast cancer, including estrogen-independent and tamoxifen-resistant cell lines which represent fatal late-stage disease. We will present our most recent findings to indicate novel modes of ER regulation that may represent potential avenues for therapy.