Activation of BTAK expression in primary ovarian surface epithelial cells of prophylactic ovaries

The ovarian epithelial cells carrying heterozygous BRCA1 or BRCA2 mutation (we called BRCA1/2 mutation) are known to predispose to the development of ovarian cancer; however, the molecular basis of such predisposition is largely unknown. We hypothesize that BTAK may be a potential target for heterozygous BRCA1/2 mutation. We sought to determine the relationship between the status of BRCA1/2 heterozygous mutation and BTAK expression in prophylactically removed ovaries as compared with normal ovaries and ovarian cancer controls. Western blot analysis of BTAK was performed in a primary cell culture carrying heterozygous BRCA1 mutation and three normal ovarian surface epithelial cell cultures. Immunohistochemical analysis of BTAK expression was also performed by image analysis in ovaries of 21 patients with known BRCA1/2 mutation or very strong family history of breast/ovarian cancer that underwent prophylactic oophorectomy, 38 normal ovaries from patients without any known mutation, and 194 ovarian carcinomas. The BTAK expression was significantly increased in primary culture carrying a heterozygous BRCA1 mutation as compared to those with no known BRCA1/2 mutation. Immunohistochemical staining of BTAK showed increased expression in ovarian epithelial cells carrying BRCA1/2 mutation or strong breast/ovarian family history compared with normal ovaries (P<0.001). Higher BTAK expression was found in ovarian cancer cells compared to ovaries without cancer but with known BRCA1/2 mutation or strong family history (P<0.001), and expression levels of BTAK and p53 were directly correlated (r=0.306; P<0.001). Increased expression of BTAK is directly correlated with mutation status of BRCA1/2 genes, suggesting that mutation in a single allele of either BRCA1 or 2 may be responsible for the activation of BTAK. This activation may be a key early genetic event in the development of hereditary ovarian cancer.