Antibody-Mediated BRCC36 Silencing: A Novel Approach for Targeted Breast Cancer Therapy

摘要

Breast tumor cells with defective BRCA1 are believed to be more sensitive to the DNA-damage based therapies. We propose that the aberrant expression (gain or loss) or activity of protein(s) in BRCA1-associated pathways will lead to a BRCA1 null-like phenotype and DNA damage hypersensitivity in breast cancer cells. BRCC36, one of the novel BRCC subunits, has been found to be associated with BRCA1 and to play an important role in the regulation of BRCC ubiquitin E3 ligase activity. We have shown that BRCC36 expression is elevated in the majority of invasive breast tumors. Importantly, we have also demonstrated that depletion of BRCC36 resulted in hypersensitivity in breast cancer cells to IR and disruption of IR-induced BRCA1 activation. Based upon these findings, we believe that BRCC36 may be an ideal target for breast cancer therapy using the siRNA gene silencing approach. In proposed studies, we will apply a cancer cell-specific or 'smart' therapeutic approach utilizing C6.5db- P/siRNA conjugates. Overall, the proposed studies will not only establish BRCC36 as a novel therapeutic target to enhance the efficacy of radiation and chemotherapy, but also help develop a novel strategy for targeting therapy aimed at improving the treatment of this prevalent and deadly disease.