Abstract 2387: Interplay between Aurora A kinase and BRCA1 promotes genetic stability
Authors: Christine M. Marion, Vanessa Yu, Louis Dubeau
Journal: Cancer Research (2014)

Abstract 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 reduced BRCA1 leads to initiation of a new cell cycle without cytokinesis, a mechanism leading to polyploidy. Aurora A kinase inhibition stabilizes the metaphase checkpoint and reduces the population of proliferating polyploid/aneuploidy cells. We propose that a similar mechanism occurs in ovarian carcinoma cells, although not readily appreciated because cells undergoing a mitotic arrest within an immortal cell culture, unlike in our mortal cystadenoma cells, are outgrown by a dividing cell population and therefore fail to accumulate. We tested this hypothesis in SKOV3 cells, a high-grade serous ovarian carcinoma line known to be P53 deficient. BRCA1 down-regulation in SKOV3 cells, similarly to ovarian cystadenoma cells, leads to polyploidy. Evidence that this is due to cytokinesis failure comes from the observation that cells with increased DNA ploidy also show multi-nucleation. BRCA1 expression increases upon Aurora A knockdown in our cell culture model. We therefore hypothesize that forced alterations in Aurora A expression may influence this process by acting, directly or indirectly, as an upstream regulator of BRCA1 expression, thereby preventing polyploidy and stabilizing the genome. Our findings raise the possibility of using Aurora A inhibition to reduce the incidence of aneuploidy in ovarian carcinomas with reduced BRCA1 expression. Minimizing the extent of aneuploidy in these tumors may delay development of treatment resistance, ultimately improving survival. Citation Format: Christine M. Marion, Vanessa Yu, Louis Dubeau. Interplay between Aurora A kinase and BRCA1 promotes genetic stability. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2387. doi:10.1158/1538-7445.AM2014-2387