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The role of the breast cancer susceptibility gene 1 (BRCA1) in sporadic epithelial ovarian cancer McCoy, Marcia L; Mueller, Christopher R; Roskelley, Calvin D Oct 7, 2003

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ralReproductive Biology and ssBioMed CentEndocrinologyOpen AcceReviewThe role of the breast cancer susceptibility gene 1 (BRCA1) in sporadic epithelial ovarian cancerMarcia L McCoy1, Christopher R Mueller2 and Calvin D Roskelley*1Address: 1Dept of Anatomy and Cell Biology, University of British Columbia, Vancouver BC, Canada and 2Cancer Research Laboratories Queens University, Kingston ON, CanadaEmail: Marcia L McCoy - mmccoy@interchange.ubc.ca; Christopher R Mueller - mueller@post.queensu.ca; Calvin D Roskelley* - roskelly@interchange.ubc.ca* Corresponding author    AbstractMutations within the BRCA1 tumor suppressor gene occur frequently in familial epithelial ovariancarcinomas 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 magnitudeof this decrease has been correlated with increased disease progression. The near absence ofsomatic mutations consequently suggests that there are alternative mechanisms that maycontribute to the observed loss of BRCA1 in sporadic tumors. Indeed, both allelic loss at theBRCA1 locus and epigenetic hypermethylation of the BRCA1 promoter play an important role inBRCA1 down-regulation; yet these mechanisms alone or in combination do not always account forthe reduced BRCA1 expression. Alternatively, misregulation of specific upstream factors thatcontrol 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 ovariantumorigenesis will lead to a better understanding of ovarian cancer etiology and it may help fosterthe future development of novel therapeutic strategies aimed at halting ovarian tumor progression.IntroductionEpithelial ovarian cancer is the most lethal of all gyneco-logical malignancies [1]. The poor survival associatedwith ovarian carcinoma is due, at least in part, to the factthat the disease is usually asymptomatic in its early stages.As a result, detection often occurs at a late, metastatic stagewhen the prognosis is poor. While the etiology of ovariancarcinogenesis is poorly understood, evidence from his-topathological studies and recently developed mousemodels of ovarian cancer progression suggest that themajority of the tumors originate from the ovarian surfaceepithelium (OSE), a simple cuboidal layer that covers thesurface of the ovary [2–5]. It remains unclear at this time,cursor that can be used to improve early detection anddiagnosis. Changes in a number of genes, including p53,k-Ras, HER2/neu and c-Myc, have been implicated inovarian carcinoma progression. However, none of thesechanges appear to occur in a stage-specific manner [6,7].While global gene profiling approaches have recentlyidentified a number of genes that are differentiallyexpressed in epithelial ovarian cancer these alterationshave not yet been be fully characterized with respect tostage, grade or functional importance [8–10]. Thus, todate, the most compelling target gene linked to the devel-opment of ovarian cancer continues to be the breast andovarian cancer susceptibility gene 1 (BRCA1).Published: 07 October 2003Reproductive Biology and Endocrinology 2003, 1:72Received: 14 July 2003Accepted: 07 October 2003This article is available from: http://www.RBEj.com/content/1/1/72© 2003 McCoy et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.Page 1 of 5(page number not for citation purposes)however, if a predictable progression of molecular eventswithin the OSE gives rise to a well-defined neoplastic pre-Reproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/72The protein products of the BRCA1 gene regulate, at leastin part, transcriptional activation, DNA repair, cell-cyclecheckpoint control, and chromosomal re-modeling [11].Such multi-faceted contributions to essential cellularfunctions imply a truly fundamental role for BRCA1 innormal development but they also confound our under-standing of its role in tumorigenesis [12]. This confusionwas initially compounded by the finding that completeBRCA1 ablation in transgenic mice blocks embryonic pro-liferation [13,14]. However, the subsequent generation ofa targeted knockout in the mouse mammary epitheliumdid result in tumor formation, which is direct experimen-tal evidence that BRCA1 can act as a tumor suppressor ina susceptible tissue [15]. While a BRCA1 knockout has notyet been targeted to the OSE there is compelling clinicalevidence that the gene is also a tumor suppressor in theovary. Drawing on parallels with the situation in thebreast, this review will focus on the possible means bywhich a non-mutational suppression of BRCA1 can beachieved in highly prevalent, non-familial, sporadic epi-thelial ovarian carcinoma.BRCA1 in familial and sporadic tumorsBRCA1 was originally isolated using positional cloningtechniques and inactivating mutations were found in fam-ilies with a high incidence of breast and ovarian cancer[16]. Specifically, germline alterations in the BRCA1 generesult in a predisposed likelihood of developing early-onset breast and ovarian cancer with a dominant pene-trance as high as 85% and 65% respectively [17]. Tumor-igenicity only occurs in these familial BRCA1heterozygotes if there is also a loss of the second wild typeBRCA1 allele. The latter observation supports the notionthat the original germline BRCA1 mutation acts reces-sively at the cellular level [18–20]. Although the presenceof an inherited mutation in one BRCA1 allele continues tobe one of the best-defined overall risk factors for thedevelopment of breast or ovarian cancer, these familialmutations, together with familial BRCA2 mutations,occur in less than 10% of all diagnosed cases [21,22]. Thegreat majority of breast and ovarian carcinomas arise spo-radically where inherited BRCA1 mutations do not occur.In addition, somatic BRCA1 mutations are virtually unde-tectable in sporadic breast cancers and they are extremelyrare in sporadic ovarian cancers [19,23–26]. Thus, at firstglance, it would not be unreasonable to conclude thatBRCA1 does not play a significant role in sporadic tumordevelopment. However, mounting evidence suggests thatalternative, non-mutational, mechanisms may suppressBRCA1 expression in these tumors [27].The first group to conclude that BRCA1 may be importantin sporadic tumor development observed a significantthat a suppression of BRCA1 activity has functional conse-quences in cultured breast carcinoma cells [28]. Sincethen, a number of studies have confirmed the associationbetween decreased BRCA1 mRNA and sporadic tumori-genesis in both the breast and the ovary [29–31]. Further-more, immunohistochemical analyses of BRCA1expression in sporadic breast and ovarian cancers revealeda significant reduction in BRCA1 protein [32,33]. Thissuppression of BRCA1 expression appears to be achievedthrough multiple means. For example, loss of heterozy-gosity (LOH) at the BRCA1 locus occurs in a significantproportion of sporadic of ovarian tumors [19,34]. Addi-tionally, 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 BRCA1protein expression. Finally, 18% of the tumors exhibiteda complete loss of BRCA1 protein in the absence of bothLOH and allelic loss [35]. Taken together, these data indi-cate that epigenetic misregulation also contributes to thereduction of BRCA1 expression in sporadic tumors.Epigenetic regulation of BRCA1Hypermethylation of the BRCA1 promoterPromoter hypermethylation is used during normal devel-opment to epigenetically downregulate gene expression ina tissue-specific manner. Methylation of the DNA occursmost frequently on the 5' cytosine residues within 5'-CpG-3' di-nucleotides, which often cluster together in CpGislands that can stretch for several kilobases [36]. Inactively transcribed genes, CpG islands within regulatoryregions are often unmethylated. In contrast, methylationat these sites represses transcription by altering chromatinstructure such that the transcriptional machinery does nothave proper access to functionally important regions ofthe promoter [37]. The proximal BRCA1 promoter lieswithin such a methylation-sensitive island and a develop-mentally inappropriate hypermethylation of the pro-moter does occur in some sporadic breast and ovariantumors [38,39]. This hypermethylation may be function-ally significant as it correlates with decreased BRCA1mRNA [40]. An important question, yet to be answered, iswhether such an abnormal promoter hypermethylation isthe cause or consequence of an initial transcriptionalrepression [41]. Regardless, promoter hypermethylationhas only been found in tumors where BRCA1 LOH hasalso occurred [40]. Thus, hypermethylation may serve asan epigenetic 'second hit' that inactivates the remainingwild type BRCA1 allele after LOH has occurred. Whileinappropriate promoter hypermethylation is very likely apowerful repressor of BRCA1 expression it is important topoint out that it only occurs in a small subset of sporadictumors [42,43].Page 2 of 5(page number not for citation purposes)decrease in BRCA1 mRNA in high grade, invasive breasttumors [28]. The same investigators also demonstratedReproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/72Transcriptional regulation of BRCA1The primary proximal BRCA1 promoter, which consists ofless than 300 base pairs (bp), lies immediately upstreamof the major breast-specific transcription start site locatedwithin the gene's first exon [44,45]. The regulation of thispromoter is complex and a number of candidate regula-tory sites have been identified and partially characterized(Fig 1). One of these elements, the positive regulatoryregion (PRR) at the 5' end of the promoter is both neces-sary and sufficient to maximally activate BRCA1 transcrip-tion [46]. Of particular interest, one putative regulatorysite located within the PRR is a cyclic-AMP response ele-ment, which is capable of specifically binding to CREB,the cyclic-AMP response element binding protein [47].Importantly, this element is a site of frequent hypermeth-ylation in breast and ovarian tumors [48] and experimen-tal methylation of this site decreases BRCA1 promoteractivity in vitro [49]. Mutation of the CREB-binding con-sensus sequence within the context of an intact BRCA1promoter [49] also causes a significant reduction in pro-moter activation in non-tumorigenic human OSE cells inculture [50]. Taken together, these findings indicate thatthe cAMP-response element is very likely an importantpositive regulator of BRCA1 expression in both the nor-mal OSE and in tumor tissue. As an initial transcriptionalrepression is capable of contributing to the later hyper-methylation of sensitive sites [41] misregulation of thetranscriptional complex that binds to the cAMP-responseelement in the BRCA1 promoter could contribute to spo-radic ovarian carcinoma development. Therefore, a care-ful examination of the signal transduction pathways thatinfluence the activity and/or binding of transcriptionalcomplexes to the cAMP-response element in the BRCA1promoter may identify potentially important oncogenicevents in sporadic ovarian carcinoma development.Schematic of the proximal BRCA1 promoter and the 8 functional sites that have been well characterized in breast cellsFigure 1Schematic of the proximal BRCA1 promoter and the 8 functional sites that have been well characterized in breast cells. The RIBS and CREB sites have recently been partially characterized in ovarian surface epithelial and in ovarian carcinoma cells (see Minimal bi-directional promoter regionEcoR1NBR2 BRCA1BRCA1 Start SiteNBR2 Start SiteETS ETS ETS CRE CAAT SP1BRAT PRFA UP?ETS-2Competes for ETS binding?ID4CREBGABPα/β tetramerRIBS ElementPositive Regulatory Region (PRR)Positive regulatory factorsNegative regulatory factorsHypermethylation sensitive sitesPage 3 of 5(page number not for citation purposes)text for details).Reproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/72It is conceivable that a number of the other transcriptionalregulators of the BRCA1 promoter may also play a role insporadic ovarian and breast carcinogenesis [27]. One suchexample is the GA-binding protein α/β (GABPα/β) whichis a member of the ETS family of transcription factors [51].GABPα/β specifically binds to three consecutive ETS fac-tor-binding domains (described as the RIBS element)located immediately upstream of the CRE element in thepositive response region (Fig 1) [52]. Transient overex-pression of GABPα/β in breast carcinoma cells is able tostimulate BRCA1 promoter transactivation, thus demon-strating that it is potentially a direct positive regulator ofBRCA1 expression [52]. Thus, loss of GABPα/β or lostresponsiveness to GABPα/β-containing transcription fac-tor complexes could result in decreased BRCA1 expressionin sporadic tumors. Indeed, the promoter binding abilityand transcriptional induction by GABPα/β is significantlyreduced in mammary carcinoma cells. Comparatively, inthe ovary the GABPα/β-binding RIBS element is highlyactive in normal OSE cells but not in ovarian carcinomacells [50]. This intriguing observation suggests that theRIBS element, and perhaps aberrant function of the fac-tors responsible for its regulation, may be specificallyimportant in the repression of BRCA1 in sporadic ovariantumors.Other DNA-binding proteins that may act on the RIBS ele-ment in the BRCA1 promoter are ID4 and ETS-2. ID4 is arecognized repressor of BRCA1 expression in both breastand ovarian carcinoma cell lines [53] that negatively reg-ulates transcription by forming heterodimers with tran-scription factors through their helix-loop-helix domain[54]. ETS-2 is a member of the ETS family of transcriptionfactors related to GABPα/β that also directly binds to theBRCA1 promoter in the RIBS domain [55]. UnlikeGABPα/β, ETS-2 overexpression represses BRCA1 tran-scription which raises the possibility that multiple ETSfactors may compete for binding within the RIBS domainsuch that upstream signaling pathways which differen-tially modulate the activation of these transcriptionalcomplexes may be the critical regulators of BRCA1expression.ConclusionTranscriptional suppression of the BRCA1 promoteroccurs in sporadic ovarian carcinoma. Clearly, hyper-methylation of the promoter plays an important role inthis process. In addition, alterations in the transcriptionfactor complexes that bind to the promoter also have arole to play, either upstream of hypermethylation or inde-pendent of it. 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