BRCA2 Status Alters the Effect of the P53 Reactivator HO-3867 in Ovarian Cancer Cells.

Abstract

The vast majority of ovarian cancers have a TP53 mutation. Among these, a substantial proportion also have a BRCA1 and/or a BRCA2 mutation. Given a rising interest in the therapeutic use of p53 reactivating agents, we assessed the effect that such BRCA mutants would have on the action of a p53 reactivator. As an initial tool to examine the effect of a BRCA mutation on the action of a p53 reactivator we chose to utilize a naturally occurring experimental model. The high grade serous ovarian cancer cell lines PEO1 and PEO4 were established from the same patient. Both cell lines have a missense TP53 mutation, G244D. However, PEO1 cells also have a nonsense BRCA2 mutation, Y1655ter, which is cancelled out by a second mutation, Y1655Y, that renders PEO4 cells BRCA2 wild-type. This makes these cell lines an ideal experimental platform to begin to assess the effect of a BRCA mutation on the action of a p53 reactivator. Both PEO1 and PEO4 cells were treated with a p53 reactivator, the synthetic curcumin analog HO-3867. The effect of treatment was assessed through quantitative PCR (qPCR) assays of fourteen known p53 target loci, including p53 itself. In all cases there was a definite difference between treated and untreated cells relative to their BRCA2 status. While these results are preliminary, the fact that BRCA2 status influences the effect of a p53 reactivator on numerous target loci suggests that this relationship should be further investigated and that, in future, the BRCA status of ovarian tumors containing missense TP53 mutations should be considered when opting for the therapeutic use of a p53 reactivator.