BRCA2 (Breast Cancer Susceptibility Gene 2) was originally identified as one of two genes responsible for familial inherited breast and ovarian cancer. Women who inherit a mutant copy of BRCA2 harbor up to a 70% lifetime risk for developing ovarian cancer. Moreover, these women carrying BRCA2 mutations are at risk for developing a particularly insidious form of ovarian cancer termed high-grade serous ovarian carcinoma. The majority of these women endure a very poor prognosis and treatment failure is all too common.
The BRCA2 protein is directly involved in a cellular process called DNA repair. Our DNA is under constant assault from both exogenous (environmental agents) and endogenous (cellular metabolism) processes that periodically result in damaged or missing DNA bases. DNA repair proteins are quality control inspectors that survey the genome for errors and then correct them. Malfunctions in DNA repair proteins can lead to a process termed “genomic instability” whereby mutations throughout the genome are accumulated at an accelerated rate. If these mutations lie in specific genes that control cellular division or death, a cell may acquire the capability to seed a tumor.
Our current understanding of how ovarian tumors originate and progress in patients with BRCA2 mutations is severely lacking. We propose to fill this gap by identifying the molecular processes that drive tumor formation in the absence of BRCA2 function. An even more ambitious goal is to ascertain whether the molecular route to cancer that BRCA2 dysfunctional cells follow can illuminate the origins of non-hereditary ovarian tumors. The foundation of our research effort is to elucidate the molecular and genetic details that underlie this lethal malignancy with an eye towards earlier detection and improved treatment. If we can identify the key players and pathways that drive ovarian tumor growth and treatment resistance, we can expose vulnerabilities that will guide the development of targeted therapies with enhanced specificity and reduced toxicity.
Dr. Ryan Jensen is an Assistant Professor in the Department of Therapeutic Radiology at the Yale School of Medicine. He joined the faculty at Yale in 2011 and recently obtained a secondary appointment in the Department of Pathology.
After graduating from U.C. Berkeley with a degree in Molecular and Cell Biology, Ryan was employed by the biotechnology company, Sugen, Inc. where he worked on signal transduction pathways involving kinases and human cancer. He then briefly worked as a technician at Stanford University where he became interested in mechanisms of DNA repair and genomic instability. Continuing with this theme of understanding how DNA damage, repair, and cancer are inter-related, Ryan spent his graduate career in the Department of Genetics at Yale unraveling a novel pathway of how cisplatin kills tumor cells. While some patients with particular tumor profiles respond favorably to cisplatin treatment, many experience resistance to the drug. Ryan and his mentor, Dr. Peter Glazer, discovered that inter-cellular communication through gap junctions could enhance the tumor killing effects of cisplatin and that this signal was mediated through the Ku/DNA-PK axis of DNA repair proteins.
During his postdoctoral training in Dr. Steve Kowalczykowski’s laboratory at U.C. Davis, Dr. Jensen succeeded in purifying the DNA repair protein, BRCA2 (breast cancer susceptibility gene 2). This work culminated in a publication in Nature describing the biochemical features of this 3,418 amino acid protein involved in homologous recombination. The role of BRCA2 in familial inherited breast cancer is well known and research on this gene has led to potent, selective therapeutic agents called PARP inhibitors. BRCA2 presents an attractive target for cancer research as mutations in this single gene lead to high lifetime risks for breast and ovarian cancer. Currently, Dr. Jensen is pursuing genetic approaches in human cells to understand how BRCA2 impinges upon ovarian cancer. Traversing the disciplines of genetics, cell biology, molecular biology, and biochemistry while maintaining a focus on the field of DNA repair will allow Dr. Jensen to pursue several different avenues for understanding the role BRCA2 plays in ovarian tumor initiation.