Ovarian cancer is a disease in which ovarian cells grow aberrantly to form a tumoral mass that can eventually evolve into a metastatic disease often incurable with current therapies. There are a number of known risk factors for ovarian cancer development including age, hormonal, reproductive and menstrual history. However, the most prominent risk factor is having a familial history of ovarian cancer and approximately 25% of all ovarian cancer cases can be attributed to hereditary factors. In particular, women with mutations in the BRCA1 gene have a 30-70% chance of developing ovarian and breast cancer by age 70. Ovarian cancer prevention for women carrying BRCA1 mutations is currently predominantly achieved through surgical strategies, such as bilateral salpingo-oophorectomy. However, these prophylactic measures are very invasive and adopting them poses a major challenge to women carrying BRCA1 mutations. Novel strategies for preventing hereditary ovarian cancer are therefore needed.
Recent scientific studies have shown that BRCA1 preserves DNA integrity when DNA is duplicated during cell division. Over the course of DNA replication, DNA lesions can spontaneously arise or be generated by exogenous damaging agents, such as UV radiation and chemical agents. DNA replication is carried out by fork-like DNA structures, known as replication forks. Replication forks are fragile DNA structures that can arrest after encountering DNA lesions and undergo collapse or degradation if not properly protected. Defective protection and inappropriate degradation of replication forks that encounter DNA lesions has been observed in BRCA1 mutant cells. These observations suggest the possibility that defects in the maintenance of replication fork stability could predispose to ovarian cancer in women with BRCA1 mutations by favoring the accumulation of genomic alterations that activate genes inducing tumor formation or inactivate genes that protect against tumorigenesis. Despite these important studies, the mechanisms by which BRCA1 protects replication forks in ovarian cells have not been elucidated.
In our previous studies we have identified key factors that stabilize replication forks stalled by DNA lesions. We now propose to investigate if these proteins or other factors that cooperate with them to protect replication forks are defectively regulated in ovarian cells carrying BRCA1 mutations. Addressing this question is important to understand how BRCA1 mutations cause genomic instability and predispose to the development of ovarian cancer. We are hopeful that our studies will lead to the development of novel preventive strategies for hereditary ovarian cancer and will significantly contribute to the reduction of ovarian cancer incidence.
Alberto Ciccia, PhD, is an Assistant Professor in the Department of Genetics and Development at Columbia University Medical Center. He holds a joint appointment in the Irving Cancer Research Center, where his laboratory is currently located. Dr. Ciccia received his master’s degree in medical biotechnology from the University of Bologna, Italy, and his PhD in Biochemistry from the London Research Institute and University College London. His post-doctoral fellowship was done at Harvard Medical School’s Department of Genetics.