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KREFTSATS-Særutlysning kreftmidler, historikk

Translational research directed toward identification of the mechanisms of chemoresistance in breast cancer.

Awarded: NOK 3.6 mill.

Our group conducts translational research with the primary aim of identifying the mechanisms of resistance to chemotherapy in breast cancer. We have concentrated our work on alterations in genes participating in the p53 and retinoblastoma protein pathway as cause of anthracycline resistance. In 1996, in collaboration with Dr. Børresen-Dales group at the Norwegian Radiumhospital we were the first to report mutations affecting the TP53 gene to predict resistance to anthracyline therapy. Now, we have identif ied also mutations affecting the p53 protein upstream gene CHEK2 (coding the chk2 protein) to be associated with anthracycline resistance, providing evidence activation by chk2 is critical to p53 activation in response to genotoxic stress in vivo. Current ly, we are exploring the effect of dominant negative chk2 splice variants in this respect. Considering the retinoblastoma pathway, we have identified epigenetic and genetic changes in multiple genes involved in this pathway with a significant correlation to lack of responsiveness to anthracycline chemotherapy. Currently, we are exploring several of these alterations with respect to functional status by in vitro assays. Following finding of correlation between BRCA1 mutations and lack of responsiveness to paclitaxel therapy, we are currently exploring alterations in other genes involved in the BRCA1 DNA-repair pathway as potential causative agents of resistance to taxane therapy. Finally, following discovery of hypermethylation of the BRCA1 promoter in som e breast tumours to be accompanied by promoter hypermethylation also in the white blood cells, in a collaborative project with Professor Gareth Evans (Manchester), we are exploring epigenetic alterations in the BRCA1 promoter as a potential non-medallion inherited trait for breast cancer.

Funding scheme:

KREFTSATS-Særutlysning kreftmidler, historikk