Abstract 2387: Interplay between Aurora A kinase and BRCA1 promotes genetic stability

Ovarian cancer accounts for 5% of all female cancer-related deaths, more than any other reproductive cancer. Of the various histological subtypes, high-grade serous carcinoma is the most common. Mutations in BRCA1/BRCA2, which are associated with familial predisposition, are present in 10% of cases, while TCGA data demonstrates that P53 is mutated in 96% of high-grade serous ovarian carcinomas. In addition to aberrant P53 expression, severe aneuploidy with a near polyploid number of chromosomes is the only other genetic abnormality associated with these tumors. Ploidy changes occur early in tumor development, suggesting that they play a crucial role in oncogenic transformation. Furthermore, severe aneuploidy is associated with poor clinical outcome in patients, presumably due to its role in treatment resistance. We used an in vitro cell culture model derived from ovarian cystadenomas, the benign counterparts of ovarian carcinomas, to investigate the molecular events leading to such ploidy changes and to develop strategies for their prevention. These cells have a non-functional P53 due to SV40 large T-antigen transfection, resulting in a genetic background similar to high-grade serous ovarian carcinomas and their precursors. We showed that these cells spontaneously undergo a mitotic arrest as they age in culture and approach in vitro crisis and that recovery from this arrest can be induced by treatment with siRNA against BRCA1. Cells become multi-nucleated suggesting that redu...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Molecular and Cellular Biology Source Type: research