Titles and Affiliations
Professor and Member, Developmental Biology Program
Professor
Weill Graduate School of Medical Sciences, Cornell University
Research area
Understanding the evolution of BRCA-related breast cancers and identifying targeted prevention strategies.
Impact
Inherited mutations in genes, including BRCA1 and BRCA2, that are involved in DNA damage repair significantly increase the risk of breast and other cancers. Normally, BRCA2 protects cells from becoming cancerous by helping them copy their DNA accurately every time they divide. It does this in three ways: by repairing breaks in DNA without introducing errors, by protecting DNA from being degraded when the copying process gets stalled, and by preventing small gaps from being left behind in newly made DNA. When BRCA2 is missing, cells accumulate DNA damage and mutations that allow tumors to form. For patients with BRCA2-mutant breast cancer, a class of targeted drugs called PARP inhibitors offers an important treatment option, but not all patients respond, and many who do eventually develop resistance. Dr. Jasin is working to gain a better understanding of why this happens.
Progress Thus Far
Dr. Jasin is testing whether high levels of estrogen, such as during normal mammary gland development, impair normal DNA replication in mammary cells. To that end, she and her team measured indicators of replication stress in DNA, a sign of insufficient DNA damage repair. She found that mammary cells at the pubertal stage experience more replication stress compared to those at the adult stage. Dr. Jasin also showed that estrogen can trigger replication stress in BRCA2-deficient cells. Her team developed 3-D mammary cell cultures to understand the molecular intricacies of the replication stress response, which is key to understanding both how BRCA2-related cancers develop and how they resist therapy. The team discovered that when gaps arise in DNA, a key tumor suppressor called p53, together with its partner p21, play central roles in how cells handle the loss of BRCA2. In other words, p53 and p21 act as cellular safeguards, allowing cells to keep copying their DNA when the process runs into trouble or slowing cells down to give them time to repair damage before dividing. This finding is especially significant because mutations in the gene encoding p53 are found in nearly every BRCA2-mutant breast tumor.
What’s next
Dr. Jasin will build on previous studies to advance our understanding of how BRCA2 and p53 and p21 cooperate to preserve genome stability under replication stress. Specifically, the team will determine which of the two safeguarding activities matters most for cells’ ability to survive the loss of BRCA2 and resist PARP inhibitor therapy. To ensure that the mechanisms they identify are directly relevant to breast tissue, they will perform similar experiments in non-cancerous breast cells. Dr. Jasin’s long-term aim is to identify which patients are most likely to benefit from current therapies as well as develop new strategies for those whose tumors no longer respond.
Biography
Maria Jasin is an investigator at Memorial Sloan Kettering Cancer Center and the Weill Cornell Graduate School of Medical Sciences, New York. She obtained her Ph.D. from the Massachusetts Institute of Technology, and was a postdoctoral researcher at the University of Zürich and Stanford University prior to joining the faculty at MSKCC.
Her research focuses on the repair of DNA breaks in chromosomes in several contexts, including during gamete development, in chromosomal translocation formation, and for gene editing, where her lab performed the first such experiment. Her understanding of DNA repair mechanisms, in particular, homologous recombination, led her laboratory to studies of the cellular roles of the breast cancer suppressors BRCA1 and BRCA2. Her studies found that both proteins are critical for homologous recombination to repair DNA breaks. Mechanistically, however, the proteins act at different steps in the pathway, such that BRCA1 and BRCA2 tumors are predicted to have both distinct and overlapping second site mutations that affect therapy resistance. Moreover, her laboratory has provided insight into the critical occurrence of replication stress arising from loss of BRCA2 and the involvement of p53. Given the high predisposition to breast cancers, a current research focus is to understand DNA repair in the breast at different developmental stages and contexts. Her research accomplishments have led to election to the National Academies of Sciences and Medicine and the American Academy of Arts and Sciences.
