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  • Original Paper
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Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer

Abstract

Wnt-1 was first identified as a protooncogene activated by viral insertion in mouse mammary tumors. Transgenic expression of this gene using a mouse mammary tumor virus LTR enhancer causes extensive ductal hyperplasia early in life and mammary adenocarcinomas in approximately 50% of the female transgenic (TG) mice by 6 months of age. Metastasis to the lung and proximal lymph nodes is rare at the time tumors are detected but frequent after the removal of the primary neoplasm. The potent mitogenic effect mediated by Wnt-1 expression does not require estrogen stimulation; tumors form after an increased latency in estrogen receptor α-null mice. Several genetic lesions, including inactivation of p53 and over-expression of Fgf-3, collaborate with Wnt-1 in leading to mammary tumors, but loss of Sky and inactivation of one allele of Rb do not affect the rate of tumor formation in Wnt-1 TG mice.

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References

  • Asano K, Merrick WC and Hershey JW. . 1997 J. Biol. Chem. 272: 23477–23480.

  • Barish GD and Williams BO. . (1999) Signal Networks and Cell Cycle Control. Gutkind JS (ed.).. Human Press.

    Google Scholar 

  • Bergstein I and Brown AMC. . (1999) Breast Cancer: Molecular Genetics, Pathogenesis and Therapeutics. Bowcock AM (ed.).. Human Press: Totowa, New Jersey pp. 181–198.

    Google Scholar 

  • Berns EM, de Klein A, van Putten WL, van Staveren IL, Bootsma A, Klijn JG and Foekens JA. . 1995 Int. J. Cancer 64: 140–145.

  • Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y, Macke JP, Andrew D, Nathans J and Nusse R. . 1996 Nature 382: 225–230.

  • Bieche I, Laurendeau I, Tozlu S, Olivi M, Vidaud D, Lidereau R and Vidaud M. . 1999 Cancer Res. 59: 2759–2765.

  • Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA and Greider CW. . 1997 Cell 91: 25–34.

  • Bocchinfuso WP, Hively WP, Couse JF, Varmus HE and Korach KS. . 1999 Cancer Res. 59: 1869–1876.

  • Brison O. . 1993 Biochim Biophys Acta 1155: 25–41.

  • Broccoli D, Godley LA, Donehower LA, Varmus HE and de Lange T. . 1996 Mol. Cell Biol. 16: 3765–3772.

  • Brown AM, Wildin RS, Prendergast TJ and Varmus HE. . 1986 Cell 46: 1001–1009.

  • Chan EF, Gat U, McNiff JM and Fuchs E. . 1999 Nat. Genet. 21: 410–413.

  • Crook T, Brooks LA, Crossland S, Osin P, Barker KT, Waller J, Philp E, Smith PD, Yulug I, Peto J, Parker G, Allday MJ, Crompton MR and Gusterson BA. . 1998 Oncogene 17: 1681–1689.

  • Cunha GR and Hom YK. . 1996 J. Mammary Gland Biol. Neoplasia 1: 21–37.

  • Daniel CW, Silberstein GB and Strickland P. . 1987 Cancer Res. 47: 6052–6057.

  • de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A and Perret C. . 1998 Proc. Natl. Acad. Sci. USA 95: 8847–8851.

  • de Lange T and DePinho RA. . 1999 Science 283: 947–949.

  • Dickson C, Smith R, Brookes S and Peters G. . 1984 Cell 37: 529–536.

  • Dietrich WF, Radany EH, Smith JS, Bishop JM, Hanahan D and Lander ES. . 1994 Proc. Natl. Acad. Sci. USA 91: 9451–9455.

  • Donehower LA, Godley LA, Aldaz CM, Pyle R, Shi YP, Pinkel D, Gray J, Bradley A, Medina D and Varmus HE. . 1995 Genes Dev. 9: 882–895.

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA, Butel JS and Bradley A. . 1992 Nature (London) 356: 215–221.

  • Edwards PA, Hiby SE, Papkoff J and Bradbury JM. . 1992 Oncogene 7: 2041–2051.

  • Elson A, Deng C, Campos-Torres J, Donehower LA and Leder P. . 1995 Oncogene 11: 181–190.

  • Faham S, Linhardt RJ and Rees DC. . 1998 Curr. Opin. Struct. Biol. 8: 578–586.

  • Fisher GH, Orsulic S, Holland EC, Hively WP, Li Y, Lewis BC, Williams BO and Varmus HE. . 1999 Oncogene 18: 5253–5260.

  • Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J, Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S, Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M et al. 1998 Am. J. Hum. Genet. 62: 676–689.

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B and Kinzler KW. . 1998 Science 281: 1509–1512.

  • Howe LR, Subbaramaiah K, Chung WJ, Dannenberg AJ and Brown AM. . 1999 Cancer Res. 59: 1572–1577.

  • Hundley JE, Koester SK, Troyer DA, Hilsenbeck SG, Subler MA and Windle JJ. . 1997 Mol. Cell Biol. 17: 723–731.

  • Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA and Weinberg RA. . 1992 Nature 359: 295–300.

  • Jakobovits A, Shackleford GM, Varmus HE and Martin GR. . 1986 Proc. Natl. Acad. Sci. USA 83: 7806–7810.

  • Jiang M, Shao ZM, Wu J, Lu JS, Yu LM, Yuan JD, Han QX, Shen ZZ and Fontana JA. . 1997 Int. J. Cancer 74: 529–534.

  • Jones JM, Attardi L, Godley LA, Laucirica R, Medina D, Jacks T, Varmus HE and Donehower LA. . 1997 Cell Growth Differ. 8: 829–838.

  • Jones JM, Cui XS, Medina D and Donehower LA. . 1999 Cell Growth Differ 10: 213–222.

  • Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW, Waldman F and Pinkel D. . 1992 Science 258: 818–821.

  • Kapoun AM and Shackleford GM. . 1997 Oncogene 14: 2985–2989.

  • Kinzler KW and Vogelstein B. . 1996 Cell 87: 159–170.

  • Ko LJ and Prives C. . 1996 Genes Dev. 10: 1054–1072.

  • Krege JH, Hodgin JB, Couse JF, Enmark E, Warner M, Mahler JF, Sar M, Korach KS, Gustafsson JA and Smithies O. . 1998 Proc. Natl. Acad. Sci. USA 95: 15677–15682.

  • Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S and Gustafsson JA. . 1996 Proc. Natl. Acad. Sci. USA 93: 5925–5930.

  • Kwan H, Pecenka V, Tsukamoto A, Parslow TG, Guzman R, Lin TP, Muller WJ, Lee FS, Leder P and Varmus HE. . 1992 Mol. Cell Biol. 12: 147–154.

  • Lammie GA, Fantl V, Smith R, Schuuring E, Brookes S, Michalides R, Dickson C, Arnold A and Peters G. . 1991 Oncogene 6: 439–444.

  • Lane TF and Leder P. . 1997 Oncogene 15: 2133–2144.

  • Lee FS, Lane TF, Kuo A, Shackleford GM and Leder P. . 1995 Proc. Natl. Acad. Sci. USA 92: 2268–2272.

  • Leppa S, Mali M, Miettinen HM and Jalkanen M. . 1992 Proc. Natl. Acad. Sci. USA 89: 932–936.

  • Li YX, Papkoff J and Sarkar NH. . 1999 Virology 255: 138–149.

  • Lijam N, Paylor R, McDonald, MP, Crawley JN, Deng CX, Herrup K, Stevens KE, Maccaferri G, McBain CJ, Sussman DJ and Wynshaw-Boris A. . 1997 Cell 90: 895–905.

  • Lin TP, Guzman RC, Osborn RC, Thordarson G and Nandi S. . 1992 Cancer Res. 52: 4413–4419.

  • Lin X and Perrimon N. . 1999 Nature 400: 281–284.

  • Liyanage M, Coleman A, du Manoir S, Veldman T, McCormack S, Dickson RB, Barlow C, Wynshaw-Boris A, Janz S, Wienberg J, Ferguson-Smith MA, Schrock E and Ried T. . 1996 Nat. Genet. 14: 312–315.

  • Lu Q, Gore M, Zhang Q, Camenisch T, Boast S, Casagranda F, Lai C, Skinner MK, Klein R, Matsushima GK, Earp HS, Goff SP and Lemke G. . 1999 Nature 398: 723–728.

  • Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS and Smithies O. . 1993 Proc. Natl. Acad. Sci. USA 90: 11162–11166.

  • MacArthur CA, Shankar DB and Shackleford GM. . 1995 J. Virol. 69: 2501–2507.

  • Mason JO, Kitajewski J and Varmus HE. . 1992 Mol. Biol. Cell 3: 521–533.

  • Massague J. . 1998 Annu. Rev. Biochem. 67: 753–791.

  • McCormack SJ, Weaver Z, Deming S, Natarajan G, Torri J, Johnson MD, Liyanage M, Reid T and Dickson RB. . 1998 Oncogene 16: 2755–2766.

  • McGuire WL and Clark GM. . 1985 Semin. Oncol. 12: 12–16.

  • McMahon AP and Bradley A. . 1990 Cell 62: 1073–1085.

  • Moolgavkar SH, Day NE and Stevens RG. . 1980 J. Natl. Cancer Inst. 65: 559–569.

  • Moser AR, Luongo C, Gould KA, McNeley MK, Shoemaker AR and Dove WF. . 1995 Eur. J. Cancer 31A: 1061–1064.

  • Moser AR, Mattes EM, Dove WF, Lindstrom MJ, Haag JD and Gould MN. . 1993 Proc. Natl. Acad. Sci. USA 90: 8977–8981.

  • Mosselman S, Polman J and Dijkema R. . 1996 FEBS Lett. 392: 49–53.

  • Motokura T, Bloom T, Kim HG, Juppner H, Ruderman JV, Kronenberg HM and Arnold A. . 1991 Nature 350: 512–515.

  • Muller WJ, Lee FS, Dickson C, Peters G, Pattengale P and Leder P. . 1990 EMBO J. 9: 907–913.

  • Nandi S, Guzman RC and Yang J. . 1995 Proc. Natl. Acad. Sci. USA 92: 3650–3657.

  • Nusse R. . 1991 Curr. Top. Microbiol. Immunol. 171: 43–65.

  • Nusse R, Brown A, Papkoff J, Scambler P, Shackleford G, McMahon A, Moon R and Varmus H. . 1991 Cell 64: 231.

  • Nusse R and Varmus HE. . 1982 Cell 31: 99–109.

  • Nusse R and Varmus HE. . 1992 Cell 69: 1073–1087.

  • Patapoutian A, Backus C, Kispert A and Reichardt LF. . 1999 Science 283: 1180–1183.

  • Penault-Llorca F, Bertucci F, Adelaide J, Parc P, Coulier F, Jacquemier J, Birnbaum D and deLapeyriere O. . 1995 Int. J. Cancer 61: 170–176.

  • Pennica D, Swanson TA, Welsh JW, Roy MA, Lawrence DA, Lee J, Brush J, Taneyhill LA, Deuel B, Lew M, Watanabe C, Cohen RL, Melhem MF, Finley GG, Quirke P, Goddard AD, Hillan KJ, Gurney AL, Botstein D and Levine AJ. . 1998 Proc. Natl. Acad. Sci. USA 95: 14717–14722.

  • Peters G, Brookes S, Smith R, Placzek M and Dickson C. . 1989 Proc. Natl. Acad. Sci. USA 86: 5678–5682.

  • Peters G, Lee AE and Dickson C. . 1986 Nature 320: 628–631.

  • Petersen OW, Hoyer PE and van Deurs B. . 1987 Cancer Res. 47: 5748–5751.

  • Pierce Jr DF, Gorska AE, Chytil A, Meise KS, Page DL, Coffey Jr RJ and Moses HL. . 1995 Proc. Natl. Acad. Sci. USA 92: 4254–4258.

  • Pike MC, Spicer DV, Dahmoush L and Press MF. . 1993 Epidemiol Rev. 15: 17–35.

  • Prives C and Hall PA. . 1999 J. Pathol. 187: 112–126.

  • Radany EH, Hong K, Kesharvarzi S, Lander ES and Bishop JM. . 1997 Proc. Natl. Acad. Sci. USA 94: 8664–8669.

  • Redston M, Nathanson KL, Yuan ZQ, Neuhausen SL, Satagopan J, Wong N, Yang D, Nafa D, Abrahamson J, Ozcelik H, Antin-Ozerkis D, Andrulis I, Daly M, Pinsky L, Schrag D, Gallinger S, Kaback M, King MC, Woodage T, Brody LC, Godwin A, Warner E, Weber B, Foulkes W and Offit K. . 1998 Nat. Genet. 20: 13–14.

  • Ricketts D, Turnbull L, Ryall G, Bakhshi R, Rawson NS, Gazet JC, Nolan C and Coombes RC. . 1991 Cancer Res. 51: 1817–1822.

  • Rimm DL, Caca K, Hu G, Harrison FB and Fearon ER. . 1999 Am. J. Pathol. 154: 325–329.

  • Robanus-Maandag E, Dekker M, van der Valk M, Carrozza ML, Jeanny JC, Dannenberg JH, Berns A and te Riele H. . 1998 Genes Dev. 12: 1599–1609.

  • Roelink H, Wagenaar E, Lopes da Silva S, and Nusse R. . 1990 Proc. Natl. Acad. Sci. USA 87: 4519–4523.

  • Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E and Polakis P. . 1997 Science 275: 1790–1792.

  • Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C and DePinho, RA. . 1999 Cell 96: 701–712.

  • Saenz Robles MT, Symonds H, Chen J and Van Dyke T. . 1994 Mol. Cell Biol. 14: 2686–2698.

  • Shackleford GM, MacArthur CA, Kwan HC and Varmus HE. . 1993 Proc. Natl. Acad. Sci. USA 90: 740–744.

  • Shackleford GM and Varmus HE. . 1987 Cell 50: 89–95.

  • Shimizu H, Julius MA, Giarre M, Zheng Z, Brown AM and Kitajewski J. . 1997 Cell Growth Differ 8: 1349–1358.

  • Shtutman M, Zhurinsky J, Simcha I, Albanese C, D'Amico M, Pestell R and Ben-Ze'ev A. . 1999 Proc. Natl. Acad. Sci. USA 96: 5522–5527.

  • Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe S, Jacks T and Van Dyke T. . 1994 Cell 78: 703–711.

  • Taylor IC, Roy S, Yaswen P, Stampfer MR and Varmus HE. . 1995 J. Biol. Chem. 270: 6872–6880.

  • Tetsu O and McCormick F. . 1999 Nature 398: 422–426.

  • Theillet C, Le Roy X, De Lapeyriere O, Grosgeorges J, Adnane J, Raynaud SD, Simony-Lafontaine J, Goldfarb M, Escot C and Birnbaum D. . 1989 Oncogene 4: 915–922.

  • Thomas KR and Capecchi MR. . 1990 Nature 346: 847–850.

  • Tsang M, Lijam N, Yang Y, Beier DR, Wynshaw-Boris A and Sussman DJ. . 1996 Dev. Dyn. 207: 253–262.

  • Tsukamoto AS, Grosschedl R, Guzman RC, Parslow T and Varmus HE. . 1988 Cell 55: 619–625.

  • Wakasugi E, Kobayashi T, Tamaki Y, Ito Y, Miyashiro I, Komoike Y, Takeda T, Shin E, Takatsuka Y, Kikkawa N, Monden T and Monden M. . 1997 Am. J. Clin. Pathol. 107: 684–691.

  • Weaver ZA, McCormack SJ, Liyanage M, du Manoir S, Coleman A, Schrock E, Dickson RB and Ried T. . 1999 Genes Chromos. Cancer 25: 251–260.

  • Wiesen JF, Young P, Werb Z and Cunha GR. . 1999 Development 126: 335–344.

  • Wilkinson DG, Bailes JA and McMahon AP. . 1987 Cell 50: 79–88.

  • Wodarz A and Nusse R. . 1998 Ann. Rev. Cell Dev. Biol. 14: 59–88.

  • Woodage T, King SM, Wacholder S, Hartge P, Struewing JP, McAdams M, Laken SJ, Tucker MA and Brody LC. . 1998 Nat. Genet. 20: 62–65.

  • Wright EG. . 1999 J. Pathol. 187: 19–27.

  • Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T, Hennighausen L, Wynshaw-Boris A and Deng CX. . 1999 Nat. Genet. 22: 37–43.

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Acknowledgements

We thank S Orsulic, S Ortiz, G Fisher and M Chamorro for critical review of the manuscript. Y Li is supported by the Department of Defense Breast Cancer Research Program.

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Li, Y., Hively, W. & Varmus, H. Use of MMTV-Wnt-1 transgenic mice for studying the genetic basis of breast cancer. Oncogene 19, 1002–1009 (2000). https://doi.org/10.1038/sj.onc.1203273

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