Ebba Kurz

Role of topoisomerase II in DNA damage detection and repair; Role of salicylates in modulating chemotherapeutic efficacy in breast cancer; Development of patient-derived tools for the study of breast cancer in young women.

Research details:  Our laboratory studies topoisomerase IIα (TOP2A) and topoisomerase IIβ (TOP2B), evolutionarily conserved enzymes that are key to untangling and unwinding intertwined strands of DNA. Faulty regulation of these processes, which can lead to genomic instability and the accumulation of mutations, can contribute to the development and spread of cancer. Topo II contributes to cell proliferation by undertaking the formidable task of separating sister chromatids prior to mitosis, as well as untangling intertwined DNA during replication and transcription. In keeping with its indispensable nature, topo II is also the target of a number of widely used anti-tumour chemotherapeutics (including doxorubicin and etoposide).

Role of topoisomerase in DNA damage detection and repair:  The importance of maintaining genomic stability is reflected in the vast number of gene products that are associated with DNA damage detection and repair; to date, more than 200 genes have been directly linked to these processes and many are conserved across eukaryotes. Given the importance of maintaining genomic stability, identification and characterization of proteins that engage in the cellular response to damaged DNA remains an ongoing area of intense investigation; our laboratory is currently exploring the role of topoisomerases in these pathways. 

Role of salicylate in modulating chemotherapeutic efficacy in breast cancer: We identified salicylate, the primary metabolite of aspirin, as a novel, isoform-selective catalytic inhibitor of TOP2A and have demonstrated that pretreatment with salicylate decreases the cytotoxicity of common TOP2-targeting chemotherapeutics in breast cancer cells. We have determined the mechanistic basis for this inhibition and are now exploring the impact of salicylates on chemotherapeutic efficacy in a breast tumour model in vivo.

Development of patient-derived tools for the study of breast cancer in young women:  Breast cancer diagnosed in women under the age of 40 is a clinically distinct entity with generally poor outcomes yet our understanding of the underlying biology is lacking. As part of the Calgary-based IN-SYNC collaboration, we are launching a pilot study to generate patient-derived tools (xenografts and organoid cultures) from young women with breast cancer to facilitate advances in research into our understanding of this disease.