PDF
ePub
Citation
Print
Abstract
Ovarian cancer is the most lethal cause of death from gynecological malignancies in the Western world. Over 90% of human ovarian cancers arise in the ovarian surface epithelium (OSE). The OSE surrounding the ovary is simple mesothelium and squamous to flat-cubobidal mesothelial cells. This cell type of ovary has both epithelial and mesenchymal potential. Also OSE cells are regulated by many factors such as cytokines, growth factors, and multiple hormones. Nevertheless OSE function is poorly understood. In particular, ovarian cancers are closely related with hereditary predisposition. Hereditary ovarian tumors are commonly associated with mutations in tumor suppressor genes such as brca1 and brca2 genes. These genes play a role in maintenance of genome integrity, DNA repair, cell cycle control and apoptosis. Mutations in brca1 and/or brca2 may lead to carcinogenesis through distinct molecular pathways like estrogen-mediated proliferation, the presence of a p53 mutation, and the modulation of the activity of NF-kB. Especially the dysfunction of brca1 triggers the inactivation of p53 and a higher proportion of a p53 mutation is commonly linked to brca-linked ovarian tumorigenesis. The dysfunction of brca1 and/or brca2 can arise from multiple mechanisms in the regulation of both JNK and ERK1/2 signaling. For more effective diagnosis and therapy of ovarian cancer, the role of brca1 and/or brca2 in ovarian cancer has to be distinctively elucidated by the animal models in which the gene functions are deleted in mouse OSE cells and by the mechanisms by which these genes affect ovarian carcinogenesis.
References
Abel, K.J., Boehnke, M., Prahalad, M., Ho, P., Flejter, W.L., Watkins, M., VanderStoep, J., Chandrasekharappa, S.C., Collins, F.S., Glover, T.W. . (. 1993. ). A radiation hybrid map of the BRCA1 region of chromosome 17q12-q21. Genomics. 17:632–641.
Alberg, A.J. and Helzlsouer, K.J. (. 1997. ). Epidemiology, prevention, and early detection of breast cancer. Curr. Opin. Oncol. 9:505–511.
Auersperg, N. (. 2003. ). Specific keynote: experimental models of epithelial ovarian carcinogenesis. Gynecol. Oncol. 88:S47–51. ; discussion. S52–45.
Auersperg, N., Edelson, M.I., Mok, S.C., Johnson, S.W. and Hamilton, T.C. (. 1998. ). The biology of ovarian cancer. Semin. Oncol. 25:281–304.
Auersperg, N., Maines-Bandiera, S., Booth, J.H., Lynch, H.T., Godwin, A.K. and Hamilton, T.C. (. 1995. ). Expression of two mucin antigens in cultured human ovarian surface epithelium: influence of a family history of ovarian cancer. Am. J. Obstet. Gynecol. 173:558–565.
Auersperg, N., Wong, A.S., Choi, K.C., Kang, S.K. and Leung, P.C. (. 2001. ). Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr. Rev. 22:255–288.
Barakat, R.R., Federici, M.G., Saigo, P.E., Robson, M.E., Offit, K. and Boyd, J. (. 2000. ). Absence of premalignant histologic, molecular, or cell biologic alterations in prophylactic oophorectomy specimens from BRCA1 heterozygotes. Cancer. 89:383–390.
Bast, R.C., Jr., Urban, N., Shridhar, V., Smith, D., Zhang, Z., Skates, S., Lu, K., Liu, J., Fishman, D. and Mills, G. (. 2002. ). Early detection of ovarian cancer: promise and reality. Cancer Treat. Res. 107:61–97.
Ben David, Y., Chetrit, A., Hirsh-Yechezkel, G., Friedman, E., Beck, B.D., Beller, U., Ben-Baruch, G., Fishman, A., Levavi, H., Lubin, F., Menczer, J., Piura, B., Struewing, J.P. and Modan, B. (. 2002. ). Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J. Clin. Oncol. 20:463–466.
Benezra, M., Chevallier, N., Morrison, D.J., MacLachlan, T.K., El-Deiry, W.S. and Licht, J.D. (. 2003. ). BRCA1 augments transcription by the NF-kappa B transcription factorby binding to the Rel domain of the p65/RelA subunit. J. Biol. Chem. 278:26333–26341.
Bennett, L.M., McAllister, K.A., Malphurs, J., Ward, T., Collins, N.K., Seely, J.C., Gowen, L.C., Koller, B.H., Davis, B.J. and Wiseman, R.W. (. 2000. ). Mice heterozygous for a Brca1 or Brca2 mutation display distinct mammary gland and ovarian phenotypes in response to diethylstilbestrol. Cancer Res. 60:3461–3469.
Boyd, J. (. 2003. ). Specific keynote: hereditary ovarian cancer: what we know. Gynecol. Oncol. 88, S8–10; discussion. S11–13.
Brodie, S.G. and Deng, C.X. (. 2001. ). BRCA1-associated tumorigenesis: what have we learned from knockout mice? Trends Genet. 17:S18–22.
Brodie, S.G., Xu, X., Qiao, W., Li, W.M., Cao, L. and Deng, C.X. (. 2001. ). Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice. Oncogene. 20:7514–7523.
Brugarolas, J. and Jacks, T. (. 1997. ). Double indemnity: p53, BRCA and cancer. p53 mutation partially rescues developmental arrest in Brca1 and Brca2 null mice, suggesting a role for familial breast cancer genes in DNA damage repair. Nat. Med. 3:721–722.
Cass, I., Baldwin, R.L., Varkey, T., Moslehi, R., Narod, S.A. and Karlan, B.Y. (. 2003. ). Improved survival in women with BRCA-associated ovarian carcinoma. Cancer. 97:2187–2195.
Chan, K.Y., Ozcelik, H., Cheung, A.N., Ngan, H.Y. and Khoo, U.S. (. 2002. ). Epigenetic factors controlling the BRCA1 and BRCA2 genes in sporadic ovarian cancer. Cancer Res. 62:4151–4156. 4151–4156.
Chandler, J., Hohenstein, P., Swing, D.A., Tessarollo, L. and Sharan, S.K. (. 2001. ). Human BRCA1 gene rescues the embryonic lethality of Brca1 mutant mice. Genesis. 29:72–77.
Chen, J., Silver, D.P., Walpita, D., Cantor, S.B., Gazdar, A.F., Tomlinson, G., Couch, F.J., Weber, B.L., Ashley, T., Livingston, D.M. and Scully, R. (. 1998. ). Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol. Cell. 2:317–328.
Choi, K.C. and Auersperg, N. (. 2003. ). The ovarian surface epithelium: Simple source of a complex disease. Minerva Ginecol. 55:297–314.
Clark-Knowles, K.V., Garson, K., Jonkers, J. and Vanderhyden, B.C. (. 2007. ). Conditional inactivation of Brca1 in the mouse ovarian surface epithelium results in an increase in preneoplastic changes. Exp. Cell Res. 313:133–145.
Deng, C.X. (. 2002. ). Tumor formation in Brca1 conditional mutant mice. Environ. Mol. Mutagen. 39:171–177.
Deng, C.X. and Brodie, S.G. (. 2001. ). Knockout mouse models and mammary tumorigenesis. Semin. Cancer Biol. 11:387–394.
Deng, C.X. and Scott, F. (. 2000. ). Role of the tumor suppressor gene Brca1 in genetic stability and mammary gland tumor formation. Oncogene. 19:1059–1064.
Deng, C.X. and Wang, R.H. (. 2003. ). Roles of BRCA1 in DNA damage repair: a link between development and cancer. Hum. Mol. Genet. 12:R113–123.
Donoho, G., Brenneman, M.A., Cui, T.X., Donoviel, D., Vogel, H., Goodwin, E.H., Chen, D.J. and Hasty, P. (. 2003. ). Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks, chromosomal instability, and reduced life span in mice. Genes Chromosomes Cancer. 36:317–331.
Dyck, H.G., Hamilton, T.C., Godwin, A.K., Lynch, H.T., Maines-Bandiera, S. and Auersperg, N. (. 1996. ). Autonomy of the epithelial phenotype in human ovarian surface epithelium: changes with neoplastic progression and with a family history of ovarian cancer. Int. J. Cancer. 69:429–436.
Flesken-Nikitin, A., Choi, K.C., Eng, J.P., Shmidt, E.N. and Nikitin, A.Y. (. 2003. ). Induction of carcinogenesis by concurrent inactivation of p53 and Rb1 in the mouse ovarian surface epithelium. Cancer Res. 63:3459–3463.
Frank, T.S. and Critchfield, G.C. (. 2001. ). Identifying and managing hereditary risk of breast and ovarian cancer. Clin. Perinatol. 28:395–406.
Fredrickson, T.N. (. 1987. ). Ovarian tumors of the hen. Environ Health Perspect. 73:35–51.
Gowen, L.C., Johnson, B.L., Latour, A.M., Sulik, K.K. and Koller, B.H. (. 1996. ). Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat. Genet. 12:191–194.
Haber, D. (. 2000. ). BRCA1: an emerging role in the cellular response to DNA damage. Lancet. 355:2090–2091.
Hakem, R., de la Pompa, J.L., Sirard, C., Mo, R., Woo, M., Hakem, A., Wakeham, A., Potter, J., Reitmair, A., Billia, F., Firpo, E., Hui, C.C., Roberts, J., Rossant, J. and Mak, T.W. (. 1996. ). The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell. 85:1009–1023.
Hartman, A.R. and Ford, J.M. (. 2002. ). BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair. Nat. Genet. 32:180–184.
Healy, B. (. 1997. ). BRCA genes–bookmaking, fortunetelling, and medical care. N. Engl. J. Med. 336:1448–1449.
Hedenfalk, I.A. (. 2002. ). Gene expression profiling of hereditary and sporadic ovarian cancers reveals unique BRCA1 and BRCA2 signatures. J. Natl. Cancer Inst. 94:960–961.
Hilton, J.L., Geisler, J.P., Rathe, J.A., Hattermann-Zogg, M.A., DeYoung, B. and Buller, R.E. (. 2002. ). Inactivation of BRCA1 and BRCA2 in ovarian cancer. J. Natl. Cancer Inst. 94:1396–1406.
Holschneider, C.H. and Berek, J.S. (. 2000. ). Ovarian cancer: epidemiology, biology, and prognostic factors. Semin. Surg. Oncol. 19:3–10.
Hosking, L., Trowsdale, J., Nicolai, H., Solomon, E., Foulkes, W., Stamp, G., Signer, E. and Jeffreys, A. (. 1995. ). A somatic BRCA1 mutation in an ovarian tumour. Nat. Genet. 9:343–344.
Jasin, M. (. 2002. ). Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Oncogene. 21:8981–8993.
Jazaeri, A.A., Yee, C.J., Sotiriou, C., Brantley, K.R., Boyd, J. and Liu, E.T. (. 2002. ). Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J. Natl. Cancer Inst. 94:990–1000.
Jonkers, J., Meuwissen, R., van der Gulden, H., Peterse, H., van der Valk, M. and Berns, A. (. 2001. ). Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat. Genet. 29:418–425.
Koul, A., Malander, S., Loman, N., Pejovic, T., Heim, S., Willen, R., Johannsson, O., Olsson, H., Ridderheim, M. and Borg, A.A. (. 2000. ). BRCA1 and BRCA2 mutations in ovarian cancer: Covariation with specific cytogenetic features. Int. J. Gynecol. Cancer. 10:289–295.
Kruk, P.A., Godwin, A.K., Hamilton, T.C. and Auersperg, N. (. 1999. ). Telomeric instability and reduced proliferative potential in ovarian surface epithelial cells from women with a family history of ovarian cancer. Gynecol. Oncol. 73:229–236.
Lalle, P., De Latour, M., Rio, P. and Bignon, Y.J. (. 1994. ). Detection of allelic losses on 17q12-q21 chromosomal region in benign lesions and malignant tumors occurring in a familial context. Oncogene. 9:437–442.
Lane, T.F., Deng, C., Elson, A., Lyu, M.S., Kozak, C.A. and Leder, P. (. 1995. ). Expression of Brca1 is associated with terminal differentiation of ectodermally and mesodermally derived tissues in mice. Genes Dev. 9:2712–2722.
Leung, P.C. and Choi, J.H. (. 2007. ). Endocrine signaling in ovarian surface epithelium and cancer. Hum. Reprod. Update. 13:143–162.
Levine, D.A., Federici, M.G., Reuter, V.E. and Boyd, J. (. 2002. ). Cell proliferation and apoptosis in BRCA-associated hereditary ovarian cancer. Gynecol. Oncol. 85:431–434.
Liu, C.Y., Flesken-Nikitin, A., Li, S., Zeng, Y. and Lee, W.H. (. 1996. ). Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. Genes Dev. 10:1835–1843.
Ludwig, T., Chapman, D.L., Papaioannou, V.E. and Efstratiadis, A. (. 1997. ). Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev. 11:1226–1241.
Ludwig, T., Fisher, P., Murty, V. and Efstratiadis, A. (. 2001. ). Development of mammary adenocarcinomas by tissue-specific knockout of Brca2 in mice. Oncogene. 20:3937–3948.
Luo, L.Y., Katsaros, D., Scorilas, A., Fracchioli, S., Bellino, R., van Gramberen, M., de Bruijn, H., Henrik, A., Stenman, U.H., Massobrio, M., van der Zee, A.G., Vergote, I. and Diamandis, E.P. (. 2003. ). The serum concentration of human kallikrein 10 represents a novel biomarker for ovarian cancer diagnosis and prognosis. Cancer Res. 63:807–811.
Maines-Bandiera, S.L. and Auersperg, N. (. 1997. ). Increased E-cadherin expression in ovarian surface epithelium: an early step in metaplasia and dysplasia? Int. J. Gynecol. Pathol. 16:250–255.
Marquis, S.T., Rajan, J.V., Wynshaw-Boris, A., Xu, J., Yin, G.Y., Abel, K.J., Weber, B.L. and Chodosh, L.A. (. 1995. ). The developmental pattern of Brca1 expression implies a role in differentiation of the breast and other tissues. Nat. Genet. 11:17–26.
Miki, Y., Swensen, J., Shattuck-Eidens, D., Futreal, P.A., Harshman, K., Tavtigian, S., Liu, Q., Cochran, C., Bennett, L.M., Ding, W. . (. 1994. ). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 266:66–71.
Moynahan, M.E. (. 2002. ). The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans. Oncogene. 21:8994–9007.
Moynahan, M.E., Pierce, A.J. and Jasin, M. (. 2001. ). BRCA2 is required for homology-directed repair of chromosomal breaks. Mol. Cell. 7:263–272.
Murdoch, W.J. and McDonnel, A.C. (. 2002. ). Roles of the ovarian surface epithelium in ovulation and carcinogenesis. Reproduction. 123:743–750.
O'Donnell, J.D., Linger, R.J. and Kruk, P.A. (. 2010. ). BRCA1 185delAG mutant protein, BRAt, upregulates maspin in ovarian epithelial cells. Gynecol. Oncol. 116:262–268.
Orsulic, S., Li, Y., Soslow, R.A., Vitale-Cross, L.A., Gutkind, J.S. and Varmus, H.E. (. 2002. ). Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. Cancer Cell. 1:53–62.
Patel, K.J., Yu, V.P., Lee, H., Corcoran, A., Thistlethwaite, F.C., Evans, M.J., Colledge, W.H., Friedman, L.S., Ponder, B.A. and Venkitaraman, A.R. (. 1998. ). Involvement of Brca2 in DNA repair. Mol. Cell. 1:347–357.
Reedy, M.B., Hang, T., Gallion, H., Arnold, S. and Smith, S.A. (. 2001. ). Antisense inhibition of BRCA1 expression and molecular analysis of hereditary tumors indicate that functional inactivation of the p53 DNA damage response pathway is required for BRCA-associated tumorigenesis. Gynecol. Oncol. 81:441–446.
Rhei, E., Bogomolniy, F., Federici, M.G., Maresco, D.L., Offit, K., Robson, M.E., Saigo, P.E. and Boyd, J. (. 1998. ). Molecular genetic characterization of BRCA1- and BRCA2-linked hereditary ovarian cancers. Cancer Res. 58:3193–3196.
Salazar, H., Godwin, A.K., Daly, M.B., Laub, P.B., Hogan, W.M., Rosenblum, N., Boente, M.P., Lynch, H.T. and Hamilton, T.C. (. 1996. ). Microscopic benign and invasive malignant neoplasms and a cancer-prone phenotype in prophylactic oophorectomies. J. Natl. Cancer Inst. 88:1810–1820.
Scully, R. and Livingston, D.M. (. 2000. ). In search of the tumour-suppressor functions of BRCA1 and BRCA2. Nature. 408:429–432.
Scully, R. and Puget, N. (. 2003. ). Hereditary breast and ovarian cancer genes. Methods Mol. Biol. 222:41–57.
Sekine, M., Nagata, H., Tsuji, S., Hirai, Y., Fujimoto, S., Hatae, M., Kobayashi, I., Fujii, T., Nagata, I., Ushijima, K., Obata, K., Suzuki, M., Yoshinaga, M., Umesaki, N., Satoh, S., Enomoto, T., Motoyama, S. and Tanaka, K. (. 2001. ). Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population. Clin. Cancer Res. 7:3144–3150.
Selvakumaran, M., Bao, R., Crijns, A.P., Connolly, D.C., Weinstein, J.K. and Hamilton, T.C. (. 2001. ). Ovarian epithelial cell lineage-specific gene expression using the promoter of a retrovirus-like element. Cancer Res. 61:1291–1295.
Shamoo, Y. (. 2003. ). Structural insights into BRCA2 function. Curr. Opin. Struct. Biol. 13:206–211.
Sharan, S.K., Morimatsu, M., Albrecht, U., Lim, D.S., Regel, E., Dinh, C., Sands, A., Eichele, G., Hasty, P. and Bradley, A. (. 1997. ). Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature. 386:804–810.
Shen, S.X., Weaver, Z., Xu, X., Li, C., Weinstein, M., Chen, L., Guan, X.Y., Ried, T. and Deng, C.X. (. 1998. ). A targeted disruption of the murine Brca1 gene causes gamma-irradiation hypersensitivity and genetic instability. Oncogene. 17:3115–3124.
Sherman, M.E., Lee, J.S., Burks, R.T., Struewing, J.P., Kurman, R.J. and Hartge, P. (. 1999. ). Histopathologic features of ovaries at increased risk for carcinoma. A case-control analysis. Int. J. Gynecol. Pathol. 18:151–157.
Somasundaram, K. (. 2003. ). Breast cancer gene 1 (BRCA1): Role in cell cycle regulation and DNA repair-perhaps through transcription. J. Cell Biochem. 88:1084–1091.
Sonoda, Y., Saigo, P.E., Federici, M.G. and Boyd, J. (. 2000. ). Carcinosarcoma of the ovary in a patient with a germline BRCA2 mutation: evidence for monoclonal origin. Gynecol. Oncol. 76:226–229.
Sundfeldt, K., Piontkewitz, Y., Ivarsson, K., Nilsson, O., Hellberg, P., Brannstrom, M., Janson, P.O., Enerback, S. and Hedin, L. (. 1997. ). E-cadherin expression in human epithelial ovarian cancer and normal ovary. Int. J. Cancer. 74:275–280.
Suzuki, A., de la Pompa, J.L., Hakem, R., Elia, A., Yoshida, R., Mo, R., Nishina, H., Chuang, T., Wakeham, A., Itie, A., Koo, W., Billia, P., Ho, A., Fukumoto, M., Hui, C.C. and Mak, T.W. (. 1997. ). Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev. 11:1242–1252.
Thakur, S., Nakamura, T., Calin, G., Russo, A., Tamburrino, J.F., Shimizu, M., Baldassarre, G., Battista, S., Fusco, A., Wassell, R.P., Dubois, G., Alder, H. and Croce, C.M. (. 2003. ). Regulation of BRCA1 transcription by specific single-stranded DNA binding factors. Mol. Cell Biol. 23:3774–3787.
Urban, N. (. 2003. ). Specific keynote: ovarian cancer risk assessment and the potential for early detection. Gynecol. Oncol. 88, S75–79; discussion. S80–73.
Venkitaraman, A.R. (. 2000. ). The breast cancer susceptibility gene, BRCA2: at the crossroads between DNA replication and recombination? Philos. Trans R. Soc. Lond. B. Biol. Sci. 355:191–198.
Venkitaraman, A.R. (. 2001. ). Functions of BRCA1 and BRCA2 in the biological response to DNA damage. J. Cell Sci. 114:3591–3598.
Venkitaraman, A.R. (. 2002. ). Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 108:171–182.
Weaver, Z., Montagna, C., Xu, X., Howard, T., Gadina, M., Brodie, S.G., Deng, C.X. and Ried, T. (. 2002. ). Mammary tumors in mice conditionally mutant for Brca1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of genomic imbalances that is similar to human breast cancer. Oncogene. 21:5097–5107.
Welcsh, P.L. and King, M.C. (. 2001. ). BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum. Mol. Genet. 10:705–713.
Werness, B.A., Afify, A.M., Bielat, K.L., Eltabbakh, G.H., Piver, M.S. and Paterson, J.M. (. 1999. ). Altered surface and cyst epithelium of ovaries removed prophylactically from women with a family history of ovarian cancer. Hum. Pathol. 30:151–157.
Wong, A.S. and Auersperg, N. (. 2003. ). Ovarian surface epithelium: family history and early events in ovarian cancer. Reprod. Biol. Endocrinol. 1, 70. Wong, A.S. and Leung, P.C. (2007) Role of endocrine and growth factors on the ovarian surface epithelium. J. Obstet. Gynaecol. Res. 33:3–16.
Wong, A.S., Leung, P.C., Maines-Bandiera, S.L. and Auersperg, N. (. 1998. ). Metaplastic changes in cultured human ovarian surface epithelium. In Vitro Cell Dev. Biol. Anim. 34:668–670.
Wong, A.S., Pelech, S.L., Woo, M.M., Yim, G., Rosen, B., Ehlen, T., Leung, P.C. and Auersperg, N. (. 2001. ). Coexpression of hepatocyte growth factor-Met: an early step in ovarian carcinogenesis? Oncogene. 20:1318–1328.
Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., Collins, N., Gregory, S., Gumbs, C. and Micklem, G. (. 1995. ). Identification of the breast cancer susceptibility gene BRCA2. Nature. 378:789–792.
Wooster, R., Neuhausen, S.L., Mangion, J., Quirk, Y., Ford, D., Collins, N., Nguyen, K., Seal, S., Tran, T., Averill, D. . (. 1994. ). Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science. 265:2088–2090.
Wright, J.W., Toth-Fejel, S., Stouffer, R.L. and Rodland, K.D. (. 2002. ). Proliferation of rhesus ovarian surface epithelial cells in culture: lack of mitogenic response to steroid or gonadotropic hormones. Endocrinology. 143:2198–2207.
Xu, C.F. and Solomon, E. (. 1996. ). Mutations of the BRCA1 gene in human cancer. Semin. Cancer Biol. 7:33–40.
Xu, X., Wagner, K.U., Larson, D., Weaver, Z., Li, C., Ried, T., Hennighausen, L., Wynshaw-Boris, A. and Deng, C.X. (. 1999. ). Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat. Genet. 22:37–43.
Xu, X., Weaver, Z., Linke, S.P., Li, C., Gotay, J., Wang, X.W., Harris, C.C., Ried, T. and Deng, C.X. (. 1999. ). Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol. Cell. 3:389–395.
Yan, Y., Haas, J.P., Kim, M., Sgagias, M.K. and Cowan, K.H. (. 2002. ). BRCA1-induced apoptosis involves inactivation of ERK1/2 activities. J. Biol. Chem. 277:33422–33430.
Yang, H., Jeffrey, P.D., Miller, J., Kinnucan, E., Sun, Y., Thoma, N.H., Zheng, N., Chen, P.L., Lee, W.H. and Pavletich, N.P. (. 2002. ). BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science. 297:1837–1848.
Yu, V.P., Koehler, M., Steinlein, C., Schmid, M., Hanakahi, L.A., van Gool, A.J., West, S.C. and Venkitaraman, A.R. (. 2000. ). Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Genes Dev. 14:1400–1406.
Figure 1.
Scheme of ovarian cancer development derived from brca1 mutation in OSE cells. The ovary is covered with simple OSE cells. These OSE cells are ruptured by ovulation and destroyed to release eggs. Ruptured OSE cells are recomposed by OSE cell proliferation. At this time, OSE cells can be created in an inclusion cyst. These inclusion cysts can more effectively be contacted with growth factors or stromal hormones by stromal layers. At results, brca1 gene appears to lead to mutation and inhibition of brca1 protein synthesis. When DNAs are damaged, deficient bara1 protein brings about scarcity of DNA repair function. Ultimately, this reason may cause the initiation of various types of ovarian tumors, i.e., serous, endometriod, mucinous, or clear cell ovarian tumors.
XML Download