Platinum compounds, such as cisplatin and carboplatin, are key drugs for the treatment of ovarian carcinoma. Both primary and acquired resistance to platinum compounds are serious clinical problems. The breast/ovarian cancer susceptibility genes BRCA1 and BRCA2 (BRCA1/2) play a critical role in repairing the DNA damage caused by platinum compounds. Consequently, BRCA 1/2-deficient cells are hypersensitive to platinum compounds. Recently, we found that platinum resistance of BRCA 1/2-mutated cancer can be mediated by secondary intragenic mutations in BRCA1/2 that restore the wild-type BRCA1/2 reading frame. Based on this finding, we hypothesize that restoration of BRCA1/2 is involved in acquired platinum resistance of BRCA1/2-deficient ovarian carcinomas. In this proposal, we focus on determining clinical relevance of restoration of BRCA1/2 function in BRCA 1/2-deficient hereditary and sporadic ovarian carcinomas. First, we will determine whether the occurrence of secondary mutations that restore DNA repair function of BRCA1/2 correlates with clinical outcomes of primary and recurrent hereditary ovarian carcinomas occurring in women with inherited BRCA1/2 mutations. Second, we will evaluate whether restoration of BRCA1 expression is involved in acquired resistance to platinum in sporadic ovarian carcinomas that initially have low BRCA1 expression before treatment. We will also determine whether ovarian cancer cells with reduced BRCA1 expression acquire restored BRCA1 function after in vitro selection in the presence of cisplatin and evaluate regulatory mechanisms that lead to restored BRCA1 expression. With these studies, we will assess the clinical significance of restoration of BRCA1/2 function during the treatment of BRCA 1/2-deficient ovarian carcinoma.
Our study will provide critical information about the mechanisms of platinum-resistance of BRCA1/2-deficient tumors, which will enable us to predict platinum resistance of recurrent tumors, and may eventually lead to the establishment of a strategy to overcome platinum resistance.
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