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. As a result, detection often occurs at a late, metastatic stage when the prognosis is poor. 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 2345. It remains unclear at this time, however, if a predictable progression of molecular events within the OSE gives rise to a well-defined neoplastic precursor that can be used to improve early detection and diagnosis. Changes in a number of genes, including p53, k-Ras, HER2/neu and c-Myc, have been implicated in ovarian carcinoma progression. However, none of these changes appear to occur in a stage-specific manner 67. While global gene profiling approaches have recently identified a number of genes that are differentially expressed in epithelial ovarian cancer these alterations have not yet been be fully characterized with respect to stage, grade or functional importance 8910. Thus, to date, the most compelling target gene linked to the development of ovarian cancer continues to be the breast and ovarian cancer susceptibility gene 1 (BRCA1).

The protein products of the BRCA1 gene regulate, at least in part, transcriptional activation, DNA repair, cell-cycle checkpoint control, and chromosomal re-modeling 11. Such multi-faceted contributions to essential cellular functions imply a truly fundamental role for BRCA1 in normal development but they also confound our understanding of its role in tumorigenesis 12. This confusion was initially compounded by the finding that complete BRCA1 ablation in transgenic mice blocks embryonic proliferation 1314. However, the subsequent generation of a targeted knockout in the mouse mammary epithelium did result in tumor formation, which is direct experimental evidence that BRCA1 can act as a tumor suppressor in a susceptible tissue 15. While a BRCA1 knockout has not yet been targeted to the OSE there is compelling clinical evidence that the gene is also a tumor suppressor in the ovary. Drawing on parallels with the situation in the breast, this review will focus on the possible means by which a non-mutational suppression of BRCA1 can be achieved in highly prevalent, non-familial, sporadic epithelial ovarian carcinoma.

BRCA1 was originally isolated using positional cloning techniques and inactivating mutations were found in families with a high incidence of breast and ovarian cancer 16. Specifically, germline alterations in the BRCA1 gene result in a predisposed likelihood of developing early-onset breast and ovarian cancer with a dominant penetrance as high as 85% and 65% respectively 17. Tumorigenicity only occurs in these familial BRCA1 heterozygotes if there is also a loss of the second wild type BRCA1 allele. The latter observation supports the notion that the original germline BRCA1 mutation acts recessively at the cellular level 181920. Although the presence of an inherited mutation in one BRCA1 allele continues to be one of the best-defined overall risk factors for the development of breast or ovarian cancer, these familial mutations, together with familial BRCA2 mutations, occur in less than 10% of all diagnosed cases 2122. The great majority of breast and ovarian carcinomas arise sporadically where inherited BRCA1 mutations do not occur. In addition, somatic BRCA1 mutations are virtually undetectable in sporadic breast cancers and they are extremely rare in sporadic ovarian cancers 1923242526. Thus, at first glance, it would not be unreasonable to conclude that BRCA1 does not play a significant role in sporadic tumor development. However, mounting evidence suggests that alternative, non-mutational, mechanisms may suppress BRCA1 expression in these tumors 27.

The first group to conclude that BRCA1 may be important in sporadic tumor development observed a significant decrease in BRCA1 mRNA in high grade, invasive breast tumors 28. The same investigators also demonstrated that a suppression of BRCA1 activity has functional consequences in cultured breast carcinoma cells 28. Since then, a number of studies have confirmed the association between decreased BRCA1 mRNA and sporadic tumorigenesis in both the breast and the ovary 293031. Furthermore, immunohistochemical analyses of BRCA1 expression in sporadic breast and ovarian cancers revealed a significant reduction in BRCA1 protein 3233. This suppression of BRCA1 expression appears to be achieved through multiple means. For example, loss of heterozygosity (LOH) at the BRCA1 locus occurs in a significant proportion of sporadic of ovarian tumors 1934. Additionally, a comprehensive study by Russell et al. 35 found that 44% of the tumors had BRCA1 allelic loss, yet, strikingly, this event did not account for the loss of BRCA1 protein expression. Finally, 18% of the tumors exhibited a complete loss of BRCA1 protein in the absence of both LOH and allelic loss 35. Taken together, these data indicate that epigenetic misregulation also contributes to the reduction of BRCA1 expression in sporadic tumors.

Transcriptional suppression of the BRCA1 promoter occurs in sporadic ovarian carcinoma. Clearly, hypermethylation of the promoter plays an important role in this process. In addition, alterations in the transcription factor complexes that bind to the promoter also have a role to play, either upstream of hypermethylation or independent of it. Therefore, the future identification of critical regulators of these complexes will point the way to functionally important signaling pathways that are co-opted during sporadic ovarian tumor formation and progression.