Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers
Abstract
Breast cancer accounts for nearly a quarter of all cancers in women, and the incidence of women being diagnosed with this disease continues to increase. Most women with breast cancer have an excellent response to surgery and first-line chemotherapies. However, many cancers recur and develop resistance to these treatments, which explains the high death rate associated with this disease. The breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 are important DNA repair genes. Individuals carrying mutations in either the BRCA1 or BRCA2 genes exhibit an increased risk of developing breast cancers. A hallmark feature of cancer cells lacking BRCA1/2 is their inability to repair damaged DNA through a complex repair mechanism known as homologous recombination (HR). HR is the primary pathway in cells for repairing DNA in an error-free manner. HR repair deficiencies, in turn, produce points of vulnerability in cancer cells by making them sensitive to DNA damaging agents such as platinum salts and poly(ADP-ribose) polymerase (PARP) inhibitors. These chemical agents have been shown to be clinically effective for the treatment for BRCA1/2-deficient tumors. However, breast cancers have been shown to acquire resistance to these drugs. Chemotherapy resistance, therefore, serves as a substantial obstacle in the long-term and effective treatment of these cancers. Resistance to chemotherapies can be established in a variety of ways. One mechanism of chemoresistance is through the re-establishment of normal DNA repair in the cancer cell. Restoration of DNA repair can itself be achieved through a variety of mechanisms. In this study, we will provide a detailed description of changes in DNA repair function during therapy and dissect the underlying mechanisms of drug resistance in breast cancer cells both with and without BRCA1 or BRCA2 mutations. A better understanding of drug resistance in breast cancer is likely to lead to new ways to overcome drug resistance and therefore more effective therapies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610599
Entities
People
- Andre Nussenzweig
Organizations
- National Cancer Institute
- United States Army