Molecular Targeting of Homologous Recombination-Deficient Breast Cancers
Abstract
Breast cancer can be caused by a combination of our environmental exposures as well as our genetic make-up. Family history of breast cancer can be used to predict whether or not individuals need additional screening or testing. We know that inactivation of some genes, such as BRCA1 and BRCA2, lead to a higher risk of breast cancer. These individuals are also at an increased risk for ovarian cancer. The inactivating changes, or DNA mutations, in BRCA1 and BRCA2 genes are well understood. However, BRCA1 and BRCA2 are not the only genes associated with breast/ovarian cancer risk. Our lab has been focusing on other genes that lead to increased breast cancer risk called RAD51C and RAD51D. Mutations in these specific genes have been observed in triple-negative breast cancers, which are typically very aggressive and difficult to treat. Currently gene panels are used to survey genes with inactivating mutations to determine if there is a connection between the mutation and breast/ovarian cancer. This connection can help explain why breast cancer developed and also inform which treatment method would be the most effective. RAD51C and RAD51D are included on these breast/ovarian cancer gene panels. To date, we have not determined which RAD51C and RAD51D mutations play a significant role in breast cancer development. Therefore, it remains unknown if the mutation caused the cancer, undermining the ability of the doctor to best treat the patient. In addition, it is unclear if related family members may also be at risk for developing breast/ovarian cancer. Our work is focused on determining which observed mutations in RAD51C and RAD51D can lead to cancer. By determining individuals at risk for developing breast cancer, this proposal directly addresses the following Overarching Challenges: (1) identify determinants of breast cancer initiation, risk, or susceptibility and (2) identify what drives breast cancer growth; determine how to stop it. To do this, we will first compile a list of all known mutations in the RAD51C and RAD51D genes found in individuals with breast/ovarian cancer. Normally, BRCA1, BRCA2, RAD51C, and RAD51D genes work together to maintain the integrity of our DNA. If these genes are inactivated, then damaged DNA cannot be repaired properly and becomes unstable. We are going to test if the mutations in RAD51C and RAD51D found in breast cancers prevent these genes from functioning, resulting in DNA instability. We predict that loss of RAD51C or RAD51D function, caused by mutations found in the breast cancer, will be a point of weakness that can be targeted with specific cancer therapies. For example, breast cancer patients with BRCA1 and BRCA2 mutations can be treated with PARP inhibitors, as this treatment takes advantage of the cancer cells’ inability to properly repair its DNA. As PARP inhibitors are a promising treatment strategy, we will test breast cancer cells with RAD51C and RAD51D mutations for PARP inhibitor sensitivity and we will extend this analysis to other similar DNA repair inhibitors. Once we identify which mutations are important for breast cancer development, we will enable better treatment options and give individuals access to the treatments they need. First, we will work toward classifying these mutations based on the standards from the American College of Medical Genetics and Genomics so that they are recognized in screening as cancer-causing. We will share this knowledge locally with the Director of the Breast and Ovarian Cancer Risk Assessment and Prevention Program at the University of Pittsburgh and nationally through our collaboration with the diagnostic company, Tempus. With Tempus’s network of 3,000-4,000 oncologists representing 30,000 patients and 55 leading cancer centers nationwide, we will be able to quickly and efficiently improve patient care. RAD51C and RAD51D are linked to hereditary breast/ovarian cancers and specifically to triple-negative breast cancers. However, the signif
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110464
Entities
People
- Kara A. Bernstein
Organizations
- United States Army
- University of Pittsburgh