Conditional genetic screens to define gene-gene and gene-drug interactions in normal and malignant human cells

Approximately eight per cent of breast cancers are caused by inherited mutations in genes called BRCA1 and BRCA2 (BReast CAncer 1 and 2). Since the BRCA genes were first identified in patients with inherited breast cancer, it has become obvious that they are also mutated in many non-inherited cancers. Understanding their function in normal and tumour cells is therefore an important problem in breast cancer research. Genes usually carry out their functions through interactions with other genes, organizing the different steps into pathways. Cells often use two or more different pathways to respond to the same stimulus. For example, there are multiple pathways that repair damaged DNA; one involves BRCA2, while a gene called PARP1 is involved in other pathways. Even when radiation and chemotherapy disable the BRCA-2 pathway, the intact PARP1 repair pathways may compensate and enable the cancer cells to survive. PARP1 inhibitors are currently undergoing clinical trials at various centres, including the BC Cancer Agency. Dr. Hong Xu is identifying interactions between the BRCA2 and PARP1 DNA repair pathways. She is also screening for gene mutations that make normal and BRCA2-mutated breast cells more sensitive to PARP1 inhibitors, which could help physicians determine appropriate doses based on a tumour’s genetic profile. Xu’s work will enhance our understanding of the roles of BRCA2 and PARP1, and accelerate the development of new individually tailored therapeutic treatments for breast cancer.