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

Abstract

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 (Po0.001). Higher BTAK expression was found in ovarian cancer cells compared to ovaries without cancer but with known BRCA1/2 mutation or strong family history (Po0.001), and expression levels of BTAK and p53 were directly correlated (r ¼ 0.306; Po0.001). 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. Keywords: BRCA heterozygous mutation; BTAK; ovarian cancer BRCA, breast cancer susceptibility gene, plays an important role in maintaining genomic stability and acts as a tumor suppressor. Mutations of BRCA1 and BRCA2 genes are associated with increased susceptibility for breast and ovarian cancer. These mutations increase the risk for developing ovarian cancer to 26% (BRCA1) and 10% (BRCA2) during a woman's lifetime. 1 Since the cloning of both genes more than a decade ago, enormous amount of work has been done to elucidate their functions. It has been shown that both BRCA1 and 2 are involved in multiple cellular pathways. 2,3 BRCA1 can arrest cell cycle progression by stimulating the transcription of the cyclin-dependent kinase (CDK) inhibitor p21 WAF/Cip1 . 4 BRCA1 also binds and works cooperatively with p53 in vivo; 5 p53, in turn, modulates BRCA1 expression. 6 BRCA-deficient cells display spontaneous chromosomal abnormalities, defective G 2 /M transit, centrosome amplification, and defects in both homologous DNA recombination and transcription-coupled base-excision repair of oxidative DNA damage. 7,8 Cells with defect...

A candidate precursor to pelvic serous cancer (p53 signature) and its prevalence in ovaries and fallopian tubes from women with BRCA mutations

“…Another report described focally intense p53 staining in the OSE of 14% of prophylactic specimens from BRCA+ women in contrast to none of controls, and linked it to expression of BTAK, which is over-expressed in immortalized human OSE cells and a high percentage of ovarian cancers. 24,25 Whether this staining pattern has biologic significance is unclear, inasmuch as we did not see evidence of DNA damage in the one p53-positive focus identified in the OSE in this study, and the p53 mutational status of these foci is unknown. Nevertheless, the experimental evidence supports a role of the OSE in the development of ovarian cancer.…”

AURKA and BRCA2 expression highly correlate with prognosis of endometrioid ovarian carcinoma

“…28 AURKA interacts with p53 and BRCA1 to regulate the cell cycle checkpoint and maintain genomic integrity by phosphorylating p53 at Ser 215 and Ser 315 (8, 9), 29,30 or BRCA1 at Ser 308 (10). 31,32 It is amplified and overexpressed in several malignant tumor types, including ovarian carcinomas. 16,33 Our results demonstrate that AURKA expression in endometrioid ovarian carcinoma is associated with poor survival, which suggests that AURKA has a role in tumorigenesis.…”

Ovarian cancer: pathology, biology, and disease models

“…BRCA1 has been shown to cooperatively bind to p53 and stimulate transcription of the cyclin-dependent kinase inhibitor p21WAF/Cip1 (19). We recently demonstrated that BTAK, a mitotic phase regulatory protein, is overexpressed in ovaries of women with a BRCA mutation or history of ovarian or breast cancer (20). Furthermore, BTAK overexpression was strongly associated with p53 overexpression, suggesting that p53 may be a physiological substrate of BTAK (20), although the underlying mechanisms of how the interaction of BRCA, p53, and BTAK regulates the initiation of ovarian tumorigenesis are not clear.…”