Maria Jasin, PhD
New York, New York
Professor, Weill Graduate School of Medical Sciences,
Member, Developmental Biology Program
Understanding the evolution of BRCA-related breast cancers and identifying ways to prevent it.
The mammary gland is highly influenced by its hormonal environment and undergoes significant changes during puberty and pregnancy. Events that occur during specific stages of mammary development, including DNA damage, are believed to alter the lifetime risk of breast cancer. Inherited mutations in genes, including BRCA1 and BRCA2, that are involved in DNA damage repair significantly increase the risk of breast and other cancers. Dr. Jasin is working to understand how developmental changes unique to the mammary gland affect the DNA damage response and how DNA repair processes in breast cells can be manipulated to create new therapeutics to prevent breast cancer, particularly in BRCA mutation carriers.
Dr. Jasin is testing whether high levels of estrogen, such as that which occurs 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. 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. Dr. Jasin and her team have grown 3D mammary cell cultures taken from different stages of development and from different BRCA2 mutants. They are using these 3-D cultures to understand the molecular intricacies of the replication stress response.
In the upcoming grant year, Dr. Jasin will expand her earlier work by performing experiments with other BRCA2 mutant cells and also probe whether progesterone, another hormone abundant in the mammary cells during development, also provokes similar outcomes. She and her team also plan to examine the role of the BRCA2 gene in puberty and pregnancy. Further, Dr. Jasin will investigate BRCA2-mutant sensitivity to two potential drug candidates, including novobiocin, an antibiotic that has been shown to be effective in cells with defective DNA repair. Results from this work will illuminate the relationship between the effects of hormone-driven replication stress and BRCA2 function in protecting the genome.
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.
When you give to BCRF, you're funding critical hours in the lab. More time for research means longer, healthier lives for the ones we love.