Oral Presentation 14th International Biennial Conference on Metastasis Research 2012

The role of RAD51 in the biology and therapeutic response of high-grade metastatic breast cancers. (#5)

Adrian P Wiegmans 1 , Fares Al-Ejeh 1 , Nicole Chee 1 , Leonard DaSilva 2 , Sarah Song 2 , Georgia Chenevix-Trench 1 , Robin Anderson 3 , Peter Simpson 2 , Sunil Lakhanni 2 , Kum Kum Khanna 1
  1. Queensland Institute of Medical Research, Brisbane, QLD, Australia
  2. UQ Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia
  3. Metastasis Research, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia

Among women with breast cancer, 30-40% will develop metastatic disease and only achieve an overall survival of less than 5 years. Despite new-targeted therapy, breast tumors that harbour similar histology or molecular phenotype differ in their response to treatment. To uncover potential new therapeutic targets and improve outcome, we performed systematic analysis of published gene expression profiling data to interrogate the expression of DNA repair genes in breast cancers. We found that high expression of the homologous recombination protein, RAD51, was significantly associated with high-grade breast cancer, aggressive subtypes and increased risk of metastasis, which was confirmed by immunohistochemistry. This provided a rationale for targeting RAD51 in high-grade, therapy-resistant breast cancers. We report for the first time a preclinical evaluation of RAD51 as a therapeutic target. In vitro that high RAD51 expressing cell lines were resistant to PARPi via enhanced DNA repair capability, while knockdown of RAD51 reversed this resistance and repressed metastatic gene expression. In-vivo, knockdown of RAD51 inhibited metastatic progression using a syngeneic breast cancer model and the seeding of human xenografts to distant sites, including brain and lung. We are currently dissecting the molecular mechanisms for RAD51-mediated pro-metastatic tumour growth that provide pre-clinical data demonstrating RAD51 as a new biomarker for metastatic progression and targeted therapy against aggressive metastatic breast cancer.