Abstract
Mutations within the BRCA1 tumor suppressor gene occur frequently in familial epithelial ovarian carcinomas but they are a rare event in the much more prevalent sporadic form of the disease. However, decreased BRCA1 expression occurs frequently in sporadic tumors, and the magnitude of this decrease has been correlated with increased disease progression. The near absence of somatic mutations consequently suggests that there are alternative mechanisms that may contribute to the observed loss of BRCA1 in sporadic tumors. Indeed, both allelic loss at the BRCA1 locus and epigenetic hypermethylation of the BRCA1 promoter play an important role in BRCA1 down-regulation; yet these mechanisms alone or in combination do not always account for the reduced BRCA1 expression. Alternatively, misregulation of specific upstream factors that control BRCA1 transcription may be a crucial means by which BRCA1 is lost. Therefore, determining how regulators of BRCA1 expression may be co-opted during sporadic ovarian tumorigenesis will lead to a better understanding of ovarian cancer etiology and it may help foster the future development of novel therapeutic strategies aimed at halting ovarian tumor progression.
Highlights
Epithelial ovarian cancer is the most lethal of all gynecological malignancies [1]
While the etiology of ovarian carcinogenesis is poorly understood, evidence from histopathological studies and recently developed mouse models of ovarian cancer progression suggest that the majority of the tumors originate from the ovarian surface epithelium (OSE), a simple cuboidal layer that covers the surface of the ovary [2,3,4,5]
Mutation of the CREB-binding consensus sequence within the context of an intact breast and ovarian cancer susceptibility gene 1 (BRCA1) promoter [49] causes a significant reduction in promoter activation in non-tumorigenic human OSE cells in culture [50]. These findings indicate that the cAMP-response element is very likely an important positive regulator of BRCA1 expression in both the normal OSE and in tumor tissue
Summary
Epithelial ovarian cancer is the most lethal of all gynecological malignancies [1]. The poor survival associated with ovarian carcinoma is due, at least in part, to the fact that the disease is usually asymptomatic in its early stages. Mutation of the CREB-binding consensus sequence within the context of an intact BRCA1 promoter [49] causes a significant reduction in promoter activation in non-tumorigenic human OSE cells in culture [50] Taken together, these findings indicate that the cAMP-response element is very likely an important positive regulator of BRCA1 expression in both the normal OSE and in tumor tissue. In the ovary the GABPα/β-binding RIBS element is highly active in normal OSE cells but not in ovarian carcinoma cells [50] This intriguing observation suggests that the RIBS element, and perhaps aberrant function of the factors responsible for its regulation, may be important in the repression of BRCA1 in sporadic ovarian tumors. Unlike GABPα/β, ETS-2 overexpression represses BRCA1 transcription which raises the possibility that multiple ETS factors may compete for binding within the RIBS domain such that upstream signaling pathways which differentially modulate the activation of these transcriptional complexes may be the critical regulators of BRCA1 expression
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