Contemplating chemosensitivity of basal-like breast cancer based on BRCA1 dysfunction

Abstract

Gene-expression profiling classified breast cancer to intrinsic subtypes, including luminal A and B, HER2 positive, normal-breast-like, and basal-like tumors. Of these, basal-like tumors that express basal cytokeratins and that are negative for estrogen receptor alpha, progesterone receptor, and HER2 show the most aggressive phenotype with a poor prognosis. Analyses of clinical samples and basic research indicate that basal-like breast cancer is caused by deficiencies in the breast cancer susceptibility protein, BRCA1. Indeed, conditionally deleting BRCA1 from the mammary gland causes mice to develop basal-like cancers at high rates. One of the major functions of BRCA1 is DNA double-strand break (DSB) repair, and its failure to perform causes increased sensitivity of cells to DNA damage-inducing agents, such as PARP inhibitors, DNA cross-linkers, or topoisomerase inhibitors. Therefore, BRCA1 dysfunction could be a principal target for therapeutic application of basal-like breast cancer. Recently, significant progress has been made in understanding the BRCA1 cascade in response to DSBs, where ubiquitin polymer formation plays critical roles. Ubiquitination was indeed found to be an apparent early response of breast cancer to neoadjuvant treatment with epirubicin and cyclophosphamide. Deducing the role of BRCA1 ubiquitin E3 ligase activity in this pathway is a critical challenge to further clarify its functional mechanism. In individualized treatment of breast cancer, evaluation of the DNA repair capacity by the BRCA1 pathway may be an important issue when determining proper treatment of basal-like breast cancer.