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Ovarian surface epithelium: family history and early events in ovarian cancer Wong, Alice S; Auersperg, Nelly Oct 7, 2003

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ralReproductive Biology and ssBioMed CentEndocrinologyOpen AcceReviewOvarian surface epithelium: family history and early events in ovarian cancerAlice ST Wong*1 and Nelly Auersperg2Address: 1Department of Zoology, University of Hong Kong, Hong Kong and 2Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, CanadaEmail: Alice ST Wong* - awong1@hku.hk; Nelly Auersperg - auersper@interchange.ubc.ca* Corresponding author    AbstractOvarian cancer is the most common cause of death from gynecological cancers in the Westernworld. There are many genetic and environmental factors which can influence a woman's risk ofgetting ovarian cancer. A strong family history of breast or ovarian cancer is definitely one of themost important and best-defined epidemiological risk factors. This review evaluates currentknowledge of hereditary ovarian cancer. Histologic, cytologic and molecular studies on the ovariansurface epithelium (OSE), which is the origin of ovarian epithelial carcinomas, from women with astrong family history for ovarian carcinomas or with a mutation in one of the two known cancersusceptibility genes – BRCA1 and BRCA2, provide a background to facilitate understanding of theearly changes in ovarian carcinogenesis. This overview is followed by a discussion of recenthypotheses and research on two questions. First, is there a mutational hotspot of BRCA mutationfor ovarian cancer? Second, why do mutations in BRCA1 and BRCA2, which are ubiquitouslyexpressed genes that participate in general cellular activities, lead preferentially to breast andovarian cancer?IntroductionOvarian surface epithelium (OSE)-derived ovarian carci-noma is the most lethal gynecological malignancy inNorth America. 5–10% of epithelial ovarian cancerinvolves strong family histories. Thus, the familial compo-nent is one of the most important and best-defined riskfactors for ovarian cancer. A woman's lifetime risk forovarian cancer is 1.4% but is estimated to be 15–60% forwomen with a strong family history and/or those whoinherited a germline mutation in certain cancer suscepti-bility genes [1,2] (see below), suggesting that thisincreased risk has a genetic component. A strong familyhistory refers to those having two or more first-degree rel-features of a type of bowel cancer (hereditary non-polypo-sis colon cancer, HNPCC, also called Lynch Syndrome II),at age 45 or younger. There are at least three types of fam-ily history of ovarian cancer indicative of a putative auto-somal dominantly inherited cancer susceptibilitysyndrome: hereditary site-specific ovarian cancer, Lynchsyndrome II and hereditary breast/ovarian carcinoma. Thediscovery of DNA mismatch repair genes such as MSH2and MLH1 for the Lynch Syndrome II [3–5], and the iden-tification of BRCA1 and BRCA2 tumor suppressor pro-teins in hereditary breast/ovarian cancer syndrome[2,6,7], have advanced our knowledge on the etiology offamilial ovarian cancer. Mutations in the BRCA1 andPublished: 07 October 2003Reproductive Biology and Endocrinology 2003, 1:70Received: 05 July 2003Accepted: 07 October 2003This article is available from: http://www.RBEj.com/content/1/1/70© 2003 Wong and Auersperg; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permit-ted in all media for any purpose, provided this notice is preserved along with the article's original URL.Page 1 of 8(page number not for citation purposes)atives (parents, siblings and children) diagnosed withbreast or ovarian cancer, and in some circumstances withBRCA2 genes, in particular, account for as much as 90%of cancers in women with familial ovarian cancer historiesReproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/70and the lifetime risk for ovarian cancer in women carryinga BRCA1 or BRCA2 mutation is estimated to be as high as60–70% [1]. The majority of BRCA1 or BRCA2 mutationsare presumed to lead to premature protein truncations asa result of frameshift deletions/insertions or nonsensemutations and alter the functions of BRCA protein.Whereas the functions of the BRCA1 and BRCA2 proteinshave yet to be fully elucidated, BRCA genes are believed tobe tumor suppressor genes, where they inhibit the growthof cancer cells through their roles in the maintenance ofgenome integrity, DNA repair, cell cycle control and apop-tosis [8].There is embryological and in vitro evidence that ovariansurface epithelium (OSE) is the origin of ovarian epithe-lial carcinomas [9]. OSE is a simple mesothelium thatoverlies the surface of the ovary. It is important to notethat the adult OSE and the Mullerian epithelia arise froma common embryonic origin, the celomic epithelium. Inearly development, OSE cells form part of the celomic epi-thelium and the celomic epithelium adjacent to the pre-sumptive gonads invaginates to give rise to the Mullerianducts, i.e. the primordia for the epithelia of the oviduct,endometrium and endocervix. The relevance of this closedevelopmental relationship between the OSE and theMullerian epithelia could explain the frequent acquisitionof architectural and functional characteristics of the Mul-lerian epithelia during neoplastic progression of OSE andthe similarities between OSE-derived carcinomas andMullerian epithelial malignancies. OSE cells from ovariesof women with strong familial history of ovarian cancerfrequently undergo Mullerian metaplasia in adult life.This will become apparent later in this review.Is there a premalignant lesion?Histologic featuresThe question, "Is there a premalignant lesion that pre-cedes the development of epithelial ovarian cancer", hasbeen addressed through four approaches: (a) comparisonof the concordance of ovarian aberrations betweenmonozygotic twins where one had ovarian cancer; (b)identifying preneoplastic changes in normal ovaries con-tralateral to unilateral ovarian cancer; (c) evaluating archi-tectural and cytologic changes of OSE adjacent toepithelial ovarian cancer; and (d) comparing the pheno-type of overtly normal ovaries, prophylactically removedfrom cancer-prone women with an inherited predisposi-tion for ovarian cancer, to normal ovaries from women ofthe general population. The first clue to the clincopatho-logical evidence was provided by Gusberg and Deligdisch(1984), who examined the grossly normal ovaries thatwere prophylactically removed from identical twin sistersof patients with invasive carcinoma of the ovary [10]. Sur-face papillations, inclusion cysts, nuclear polymorphismor stratification in surface and invaginated epithelial lin-ing are frequently found in these ovaries. All of these char-acteristics have been postulated by various investigators tobe potentially premalignant histologic features. Other ear-lier studies using both light microscopy and image cytom-etry have reported similar cellular and nuclear atypia inthe non-cancerous OSE or cyst epithelium adjacent to pri-mary ovarian tumors [11,12].Ovaries from BRCA mutation carriers provide an excellentopportunity to identify candidate lesions for the study ofearly molecular changes in ovarian carcinogenesis,because these women are at a significant risk for develop-ing ovarian cancer compared to women without such aTable 1: Histopathologic alterations of ovaries from women with family history of ovarian cancerPresent AbsentHistologicMetaplasia of surface epithelium [13] [14–17]PapillomatosisStratificationEpithelial inclusion cystsInvaginationsStromal hyperplasia [13] [14,15]CytologicNuclei of the surface epithelium [14,16,18]Larger nucleiIrregular contoursHeterogenous dense chromatinMolecularIncreased expression of p53, c-erbB and Ki-67 [15,19]Page 2 of 8(page number not for citation purposes)Reproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/70family history (Table 1). Salazar et al. (1996), in a non-blinded study of 20 high-risk individuals and 20 womenwith no family history of ovarian cancer, revealed a higherrate of potentially preneoplastic features such as surfacepapillomatosis, surface epithelial stratification, epithelialinclusion cysts, invaginations and ovarian stromal hyper-plasia in prophylactically removed ovaries from high-riskindividuals [13]. Although only 9 of the 20 women stud-ied by Salazar et al. (1996) have documented germlineBRCA1 mutations, the study provides us with valuableinformation on phenotypic alterations in ovarian tissuesdue to hereditary influences. The positive family history ofbreast/ovarian cancer strongly suggests that most if not allof these women carry mutations in the BRCA1 or BRCA2genes, even though they are not tested. The study alsoidentified two unanticipated microscopic ovarian neo-plasms in these high-risk ovaries. Consistent with thesedata, Werness et al. (1999) reported an increased fre-quency of inclusion cysts in a blinded study of 64 prophy-lactic oophorectomy specimens removed from womenwith a strong family history of ovarian cancer compared to30 controls [14]. In contrast, 3 blinded studies on prophy-lactically removed ovaries from BRCA1 and BRCA2 muta-tion carriers found no significant difference in these earlymorphologic features related to ovarian carcinogenesis[15–17]. On the other hand, the blinded histopathologicanalysis of Werness et al. (1999) revealed an importantfinding: although no microscopic (pre)malignant featuressuch as papillomatosis and increased stromal activitieswere found, image analysis identified changes in thenuclei, where those from the ovaries of high-risk individ-uals were larger, of irregular contours, and containedmore heterogeneously dense chromatin than nuclei ofcontrol ovaries [14]. Similarly, precancerous changes inthe nuclei of high-risk ovaries were demonstrated by anovel computational analysis in the study of Deligdisch etal. (1999), which focused on BRCA founder mutations inJewish patients [18]. 77.6% of ovaries removed fromwomen of Ashkenazi Jewish descent who are at high riskfor ovarian cancer because of the prevalence of BRCA1mutations showed significantly larger nuclei and non-homogenous chromatin distribution than in control ova-ries. Similar nuclear atypia was also identified in the non-cancerous surface epithelium adjacent to primary ovariantumors compared to OSE from control ovaries [12]. How-ever, there is no evidence of premalignant alterations intumor suppressor proteins and oncogenes, such as thep53 tumor suppressor protein and the c-erbB2 oncopro-tein, which are most frequently implicated in ovarian car-cinogenesis, between OSE or cyst epithelium of ovariesfrom women with inherited BRCA1 mutations and con-trols. Neither was there a difference in cell proliferationand apoptosis [15,19].It is noteworthy that surface invaginations and inclusioncysts are more frequent in high-risk ovaries than in controlovaries. This is an exciting prospect because the ovariansurface epithelium (OSE) is normally separated from theovarian stroma by the tunica albuginea, and the entrap-ment of the OSE cells within the stroma to form inclusioncysts generates a microenvironment in which the OSE is inclose proximity to the paracrine influence of adjacentovarian cortical stroma. Such epithelial-stromal interac-tion is important for epithelial differentiation, and mayaccount for the Mullerian metaplasia commonly seen inthe inclusion cysts. This hypothesis is supported by theobservation that tubal epithelial metaplasia was fre-quently present in inclusion cysts of ovaries contralateralto ovaries containing unilateral carcinomas compared tocontrol ovaries [20,21]. It has been postulated that meta-plastic and dysplastic changes of cyst-lining OSE cellscould also be promoted by increased levels of estrogen,growth factors and bioactive cytokines in cyst fluid.In cultureIt is interesting that OSE of women with strong family his-tories of breast and ovarian cancer differs not only geneti-cally but also phenotypically from OSE of women with nosuch family history (Table 2). Normal OSE is a mesothe-lium of an uncommitted phenotype. It is a simple squa-mous-to-cuboidal epithelium in vivo. In tissue culture,normal OSE cells are highly responsive to environmentalsignals and have a tendency to undergo epithelio-mesen-chymal conversion over time. In contrast to OSE cellsfrom women in the general population (NFH-OSE) thatbecome mesenchymal after a few passages, OSE cells fromwomen with strong family history of breast/ovarian can-cer (FH-OSE) retain predominantly epithelial morpholo-gies and growth patterns. Furthermore, FH-OSE cells areunable to contract three-dimensional sponge matrices,suggesting that these cells are more committed to epithe-lial differentiation and less responsive to wound-healingstimuli such as those associated with ovulation [22]. Theovarian carcinoma cell lines show an even more commit-ted epithelial phenotype. Another (pre)neoplastic charac-teristic of FH-OSE in culture is to form colonies withwhorls of elongated, irregularly shaped overlapping cellsin primary culture, which appear to be metaplastic [23].These altered morphologic features are concomitant withinappropriate expression of epithelial differentiationmarkers. FH-OSE cultures contained more cytokeratinand less mesenchymal collagen type III than NFH-OSE[22]. Two of the more important indications to suggest anincreased commitment to an epithelial phenotype inovertly normal OSE cells from women with family histo-ries of ovarian cancer (FH-OSE) is the enhanced expres-Page 3 of 8(page number not for citation purposes)sion of CA125 [24] and E-cadherin [25]. CA125 and E-cadherin are epithelial differentiation markers, whichReproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/70have little if any expression in normal human OSE, butare prominent in ovarian epithelial-lined clefts andinclusion cysts, Mullerian epithelia, for example oviductaland endometrial epithelia, and in ovarian carcinomas.The high intensity and number of cells expressing bothmarkers also relate to the embryonic proximity of OSE toMullerian duct epithelia. The malignant tumors oftenhave histologic features that are reminiscent of the archi-tecture and function of epithelia of the oviduct,endometrium and endocerix. It is interesting that the dis-tributions of E-cadherin and CA125 in culture were simi-lar, although there is no evidence that the functions ofthese two cellular components are related.While the presence of hormone and growth factor recep-tors of OSE and their ability to secrete cytokines andgrowth factors is an integral part in normal OSE physiol-ogy, the cells appear to become less responsive to environ-mental signals and engaged into dysregulated autocrineloops with malignant progression. For example, macro-phage-colony stimulating factor (M-CSF) is secreted bynormal OSE cells and acts in a paracrine manner butbecome an autocrine regulatory factor in ovarian cancercells, which also express its receptor [26,27]. Importantly,FH-OSE cells produce hepatocyte growth factor (HGF)which acts as an autocrine growth regulator in other ovar-ian carcinoma cell lines, but rarely by normal OSE (9%).61% of FH-OSE cultures express HGF and Met receptorconcomitantly [28]. Several signaling molecules, includ-ing those of the phosphoinositol-3-kinase pathway arealready activated in FH-OSE cultures independent ofexogenous growth factor stimulation, which could beattributed to the autocrine HGF-Met regulation in thesecells or other cytokines and growth factors. It is also pos-sible that the PI3KCA gene which could lead to increasedphosphoinositol-3-kinase activity is already amplified inPerhaps one of the most interesting observations in thesestudies is that FH-OSE has a more limited growth poten-tial and tends to senescence earlier than NFH-OSE in cul-ture. This appears at a first glance to be different from theincreased cell growth that confers tumorigenesis, but isparticularly relevant to the paradoxical acquisition ofMullerian epithelial differentiation in early stages of ovar-ian neoplastic progression. As discussed earlier, most FH-OSE cultures have a propensity to undergo metaplasia toa Mullerian phenotype under physiological conditions,however routine culture condition does not supportexpansion of these transformed characteristics. Thus, thedifferentiated, metaplastic surface epithelium tends tosenescence earlier in culture. Alternatively, the metaplasticphenotype may be reversible and is lost in culture,because causative factors, present in vivo, are missing. Ashorter telomeric length of FH-OSE than NFH-OSE cellsmay provide an alternative explanation to the reducedgrowth potential in these cells [31]. Loss of telomere pro-tection which represents a greater proximity to cell senes-cence and a decrease in genomic stability could contributeto the earlier age of onset of ovarian cancer in women withfamilial ovarian cancer syndromes.Although the populations chosen for comparative studiesare likely to represent cancer-prone and non cancer-pronegroups have some limitations. First, it is difficult to accu-rately define the risk of ovarian cancer. Women in the gen-eral population who are carriers of BRCA mutations maybe at a greater risk for ovarian cancer due to genetic rea-sons, however this does not account for other known non-genetic factors such as reproductive history and use of oralcontraceptives. Similarly, the control population may notbe a pure low-risk population, since in most studies nei-ther extensive family history analysis nor BRCA1 testinghas been performed on these women. Second, it is diffi-Table 2: Phenotypic differences of NFH-OSE and FH-OSE in cultureNFH-OSE FH-OSEResponse to environmental signals greater lesserGrowth potential greater lesserTelomeric length longer shorterMetaplastic colonies in primary culture rare frequentExpression ofCA125 rare prominentE-cadherin rare prominentHigh molecular weight keratin less moreCollagen III more lessCoexpression of HGF and Met receptor rare frequentSignaling pathways (such as PI3K) non-activated activatedPage 4 of 8(page number not for citation purposes)FH-OSE cells [29], similar to the amplification of this genein many ovarian cancers [30].cult to control statistically for age differences between thehigh-risk cases and controls. Because familial ovarianReproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/70cancer is diagnosed at a younger age than sporadic ovariancancer, women who decide to have their ovaries removedprophylactically to prevent the development of ovariancancer are typically young, usually before age 45 as soonas childbearing is completed. Ovaries are very rarelyremoved from women at this young age under any othercircumstances.BRCA-associated ovarian tumorsMany studies have sought to determine potential serumbiomarkers by comparing expression patterns of ovariancarcinomas and normal human OSE cells using high-throughput genomic and proteomic technologies [32,33].Important to this review, Jazaeri et al. (2002) used micro-array technology to examine the role of mutations in theBRCA1 and BRCA2 genes in ovarian carcinogenesis bycomparing gene expression patterns in ovarian cancersthat are associated with germline BRCA1 and BRCA2mutations and sporadic ovarian cancers [34]. Interest-ingly, BRCA1 and BRCA2-associated ovarian tumors dis-play distinct gene expression profiles. 110 genes showedstatistically significant different expression levels. Thisresult suggests that BRCA1 and BRCA2 have differentfunctions in ovarian carcinogenesis even though bothproteins have been implicated in DNA damage repair,chromatin remodeling and transcriptional regulation.These data are in agreement with a previous study illus-trating differences in gene expression profiles in BRCA1and BRCA2-linked breast cancer [35]. The second impor-tant finding is that the molecular profiles of hereditaryand sporadic ovarian cancers are not significantly differ-ent; sporadic ovarian tumors shared gene expression fea-tures of either the BRCA1 or BRCA2-associated tumors.The parallels in hereditary and sporadic ovarian tumorphenotypes suggest that sporadic tumors may also resultfrom epigenetic loss of BRCA functions through inactiva-tion of the BRCA1 or BRCA2 genes. Although mutationsof BRCA genes are rare in sporadic ovarian tumors, loss ofBRCA function through high rates of loss of heterozygos-ity, hypermethylation of the BRCA promoter or othermechanisms is a frequent event in sporadic ovariantumors [36]. These alternate pathways may play a role inthe loss of function of BRCA1 or BRCA2 which is requiredfor the disease phenotype to develop. Consistently,decreased expression of BRCA1 in the nucleus is observedin sporadic ovarian tumors, suggesting defects in normalnuclear function of this protein [37,38]. It is also possiblethat the molecular mechanisms in sporadic tumors arealtered in a similar way as in BRCA-associated ovariantumors. It has been suggested that there are other overrid-ing key pathways driving ovarian cancers, which are as yetundescribed [39]. Although the clinical and pathologicalfeatures of ovarian cancers in women with inherited germ-[40], ovarian cancers arising from BRCA1 or BRCA2 muta-tion-positive families are more likely to be invasive, highgrade and of serous histologic type than cancers arising inwomen without BRCA mutations [40,41].Is the relative risk for ovarian cancer associated with the location of BRCA mutations?Although there is little evidence for mutational hotspotsor clustering on BRCA1 and BRCA2 genes except in certainpopulations, e.g. Ashkenazi Jewish, a defined repertoire ofmutations have been detected, it has been suggested thatthe location of BRCA mutations is associated with differ-ent ovarian cancer risk. Mutations at the C-terminal ofBRCA1 protein appear to be associated with breast cancer,whereas mutations at the N-terminal of the protein aremore strongly associated with ovarian cancer [42]. TheRING-finger domain of the N-terminus of BRCA1 proteinappears to play a role in the anti-apoptotic function inOSE cells [43]. Among BRCA2 mutation carriers, the riskof ovarian cancer is greatest for women with mutationsclustered in a region of 3.3 kb in exon 11 [44]. However,other genetic and environmental factors are also impor-tant. For example, rare alleles of HRAS1 have been shownto increase the risk for ovarian cancer at least two times inwomen with the same BRCA1 mutation [45]. Rare HRAS1alleles also contribute to a greater risk of ovarian cancer inthe general population [46]. Preliminary data suggest thatthe 17β-hydroxysteroid dehydrogenase-2 gene may func-tion as a linked modifier of ovarian cancer risk in BRCA1mutation carriers [47].The nature of germline BRCA1 and BRCA2 mutations areto some extent dependent on the ethnicity of the popula-tion [see review in [48]]. The most notable example ofmutations in these genes is the Ashkenazi Jewish womenwith early-onset ovarian cancer (and breast cancer), wheretwo specific mutations in BRCA1 (185del AG and538insC) and one mutation in BRCA2 (6174delT) appearto be particularly common. While another BRCA2999del5 mutation is more common to the Icelandic pop-ulation and a unique BRCA1 mutation (3452delA) wasidentified in two women diagnosed with ovarian cancerfrom Mongolia, a geographically isolated population.Gender and tissue-specific propertiesAlthough germline BRCA1 or BRCA2 mutations arepresent in all tissues and BRCA proteins exhibit funda-mental cellular functions in maintaining genomic integ-rity, mutations in BRCA strongly predispose for breast andovarian cancers in women. There are two possible hypoth-eses to explain why mutations in BRCA1 and BRCA2 leadspecifically to breast and ovarian cancer: first, the loss of asecond allele of BRCA preferentially occurs in women, inPage 5 of 8(page number not for citation purposes)line BRCA1 and BRCA2 mutations compared to ovariancancers that arise sporadically have been less consistentwhom breast and ovarian tissues are preferred sites, butwhat causes this preferential loss is not known. Second,Reproductive Biology and Endocrinology 2003, 1 http://www.RBEj.com/content/1/1/70the putative tissue-specific activities of BRCA, such as itseffect on hormone functions, may favor transformation inhormone-responsive epithelial tissues. Beginning inpuberty, both the breast and ovarian epithelium prolifer-ate rapidly in response to changes in levels of estrogen.Reproductive factors linked to estrogen, such as oral con-traceptive use, are associated with breast and ovarian can-cer risk.A recent study by Ganesan et al. (2002) may provide someinsights to the question of why BRCA1 mutation is a pre-disposing factor for hereditary cancer syndromes morefrequently in women than in men. BRCA1 is found tocontribute to the X-chromosome inactivation, which is aprocess specific to female cells [49]. Moreover, breast andovarian carcinoma cells lacking BRCA1 show evidence ofdefects in X-chromatin structure. Such defects could bereversed by the expression of wild-type BRCA1 [49]. Insupport of this model, a preliminary study suggests that X-inactivation may not be a random process in women withBRCA1 mutations. Interestingly, the process is in someways favorably occurring on the alternative X-chromo-some carrying the wild-type BRCA1 allele [50]. This sug-gests that the combination of a germline mutation of theBRCA1 gene as well as nonrandom X-chromosome inacti-vation could eliminate wild-type activity of this gene andthus contributes to the increased incidence of cancer inthese females. However, further experiments will berequired to verify this issue. It is also intriguing to askwhether such properties could be related to the abnormalnuclear structure seen in high-risk ovaries described ear-lier in this review [14,18].BRCA1 has been reported to interact with the estrogenreceptor (ER) and inhibit both ligand-dependent and -independent ER activation [51,52]. Estrogen is a principaldeterminant in the epithelial cell proliferation, differenti-ation and normal functional status of breast and ovary,which are both estrogen-responsive organs. Therefore,BRCA1 mutations might possibly promote the growthand differentiation of ovarian and mammary epithelialcells through regulation of estrogen receptor activity, andby implication, contribute to the initiation of ovarian andbreast cancer. However, it seems confusing that BRCA1mutations have never been linked to tumors of otherestrogen-responsive tissues, including the endometrium.Alternatively, not mutually exclusive with the modeldescribed above, certain oxidative forms of estrogen havebeen reported to be genotoxic [53], and BRCA1 has beenproposed to play a role in protecting breast and ovariantissue from estrogen-induced DNA damage. BRCA1 hasalso been documented to enhance androgen-dependenttransactivation by androgen receptor [54], allelic variantsBRCA1-/- mouse embryos exhibit early embryoniclethality, which hinders the study of the tumor suppres-sion activity of BRCA1 [56]. Mice heterozygous for muta-tions in either the BRCA1 or BRCA2 gene have beengenerated. Although these mice are not predisposed tomammary or ovarian tumor development, they displaydefects in mammary duct branching and atrophic ovarieswith significantly arrested follicular development inresponse to estrogen [57]. The incidence of breast tumorsincreases when the mice were crossed into a p53+/- back-ground [58], consistent with the idea that loss of BRCAgene alone is not sufficient to confer tumor formation andrequires the accumulation of addition mutations in genesfor checkpoint controls, including the inactivation of p53.ConclusionOne reason for the high mortality of ovarian cancer is thatalmost 70% of the disease is diagnosed at a late stagewhen disease has spread beyond pelvis. However, if awoman is diagnosed with an early stage (stage I) ovariancancer, the survival rate is close to 90% without alteringcurrent therapeutic approaches. Data presented in thisreview suggest that ovaries removed prophylactically fromwomen with familial ovarian cancer syndromes mayappear macroscopically normal; however, a careful his-topathological examination may reveal a number of can-cer-prone phenotypes and perhaps even unanticipatedmalignant neoplasms. 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