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  • Original Paper
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Inactivation of Apc perturbs mammary development, but only directly results in acanthoma in the context of Tcf-1 deficiency

Oncogene volume 21, pages 6446–6457 (2002)Cite this article

Abstract

Apc (adenomatous polyposis coli) encodes a tumour suppressor gene that is mutated in the majority of colorectal cancers. Recent evidence has also implicated Apc mutations in the aetiology of breast tumours. Apc is a component of the canonical Wnt signal transduction pathway, of which one target is Tcf-1. In the mouse, mutations of both Apc and Tcf-1 have been implicated in mammary tumorigenesis. We have conditionally inactivated Apc in both the presence and absence of Tcf-1 to examine the function of these genes in both normal and neoplastic development. Mice harbouring mammary-specific mutations in Apc show markedly delayed development of the mammary ductal network. During lactation, the mice develop multiple metaplastic growths which, surprisingly, do not spontaneously progress to neoplasia up to a year following their induction. However, additional deficiency of Tcf-1 completely blocks normal mammary development and results in acanthoma.

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References

  • Bienz M, Clevers H . 2000 Cell 103: 311–320

  • Bradbury J, Edwards P, Niemeyer C, Dale T . 1995 Dev. Biol. 170: 553–563

  • Brisken C, Park S, Vass T, Lydon JP, O'Malley BW, Weinberg RA . 1998 Proc. Natl. Acad. Sci. USA 95: 5076–5081

  • Brisken C, Heineman A, Chavvaria T, Elenbaas B, Tan J, Dey S, McMahon J, McMahon A, Weinberg R . 2000 Genes Dev. 14: 650–654

  • Buckholm I, Nesland J, Borresen-Dale A-L . 2000 J. Pathol. 190: 15–19

  • Cadigan K, Nusse R . 1997 Genes Dev. 11: 3286–3305

  • Cardiff R, Anver M, Gusterson B, Hennighausen L, Jensen R, Merino M, Rehm S, Russo J, Tavassoli F, Wakefield L, Ward J, Green E . 2000 Oncogene 19: 968–988

  • Callahan R, Smith GH . 2000 Oncogene 19: 992–1001

  • Chapman R, Laurenco P, Tonner E, Flint D, Selbert S, Takeda K, Akira S, Clarke AR, Watson CJ . 1999 Genes Dev. 13: 2604–2616

  • Edwards PAW, Hiby S, Papkoff J, Bradbury JM . 1992 Oncogene 7: 2041–2051

  • Fearnhead NS, Britton MP, Bodmer WF . 2001 Hum. Molec. Genetics 10: 721–733

  • Furuuchi K, Tada M, Yamada H, Kataoka A, Furuuchi N, Hamada J, Takahashi M, Todo S, Moriuchi T . 2000 Am. J. Pathol. 156: 1997–2005

  • Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertson H, Joslyn G, Stevens J, Spirio L, Robertson M . 1991 Cell 66: 589–600

  • Guger KA, Gumbiner BM . 2000 Dev. Biol. 223: 441–448

  • Gu H, Marth J, Orban P, Mossman H, Rajewsky K . 1994 Science 265: 103–106

  • He T-C, Sparks A, Rago C, Hermeking H, Zawel L, da Costa L, Morin P, Vogelstein B, Kinzler KW . 1998 Science 281: 1509–1512

  • He T-C, Chan TA, Vogelstein B, Kinzler KW . 1999 Cell 99: 335–345

  • Ho K, Kalle W, Lo THS, Lam W, Tang C . 1999 Histopathology 35: 249–256

  • Imbert A, Eelkema R, Jordan S, Feiner H, Cowin P . 2001 J. Cell Biol. 153: 555–568

  • Ishitani T, Ninomiya-Tsuji J, Nagai S, Nishita M, Meneghini M, Barker N, Waterman M, Bowerman B, Clevers H, Shibuya H, Matsumoto K . 1999 Nature 399: 798–802

  • Jin Z, Tamura G, Tsuchiya T, Sakata K, Kashiwaba M, Osakabe M, Motoyama T . 2001 Br. J. Cancer 85: 69–73

  • Kashiwaba M, Tamura G, Ishida M . 1994 J. Cancer Res. Clin. Oncol. 120: 727–731

  • Kordon EC, Smith GH . 1998 Development 125: 1921–1930

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

  • Lin S-Y, Xia W, Wang J, Kwong K, Spohn B, Wen Y, Pestell R, Hung M-C . 2000 Proc. Natl. Acad. Sci. USA 97: 4262–4266

  • Michaelson JS, Leder P . 2001 Oncogene 20: 5093–5099

  • Midgley CA, White S, Howitt R, Save V, Dunlop MG, Hall PA, Lane DP, Wyllie AH, Bubb VJ . 1997 J. Pathol. 181: 426–433

  • Miyoshi K, Shillingford JM, Le Provost F, Gounari F, Bronson R, von Boehmer H, Taketo MM, Cardiff RD, Hennighausen L, Khazaie K . 2002 Proc. Natl. Acad. Sci. USA 99: 219–224

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

  • Moser AR, Shoemaker AR, Connelly CS, Clipson L, Gould KA, Luongo C, Dove WF, Siggers PH, Gardner RL . 1995 Dev. Dyn. 203: 422–433

  • Moser R, Hegg F, Cardiff RD . 2001 Cancer Res. 61: 3480–3485

  • Nathke I, Adams C, Polakis P, Sellin J, Nelson WJ . 1996 J. Cell Biol. 134: 165–179

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

  • Polakis P . 2000 Genes Dev. 14: 1837–1851

  • Pollack AL, Barth AI, Altschuler Y, Nelson WJ, Mostov KE . 1997 J. Cell Biol. 137: 1651–1662

  • Roose J, Molenaar M, Peterson J, Hurenkamp J, Brantjes H, Moerer P, van de Wetering M, Destree O, Clevers H . 1998 Nature 395: 608–612

  • Roose J, Clevers H . 1999 Biochim. Biophys. Acta 87456: M23–M37

  • Roose J, Huls G, van Beest M, Moerer P, van der Horn K, Goldschmeding R, Logtenberg T, Clevers H . 1999 Science 285: 1923–1926

  • Schlosshauer P, Brown S, Eisenger K, Yan Q, Guglielminetti E, Parsons R, Ellenson L, Kitajewski J . 2000 Carcinogenesis 21: 1453–1456

  • Selbert S, Bentley D, Melton D, Rannie D, Laurenco P, Watson C, Clarke AR . 1998 Transgenic Res. 7: 387–396

  • Shibata H, Toyama K, Shioya H, Ito M, Hirota M, Hasegawa S, Matsumoto H, Takano H, Akiyama T, Toyoshima K, Kanamaru R, Kanegae Y, Sarb I, Nakamura Y, Shiba K, Noda T . 1997 Science 278: 120–123

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

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

  • Soriano P . 1999 Nat. Genet. 21: 70–71

  • Smits R, Kielman M, Breukel C, Zurcher C, Neufeld K, Jagmohan-Changur S, Hofland N, van Dijk J, White R, Edelmann W, Kucherlapati R, Khan PM, Fodde R . 1999 Genes Dev. 13: 1309–1321

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

  • Thompson A, Morris R, Wallace M, Wyllie A, Steel C, Carter D . 1993 Br. J. Cancer 68: 64–68

  • Tsukamoto A, Grosschedl R, Guzman R, Parslow T, Varmus H . 1988 Cell 55: 619–625

  • Wang TC, Cardiff RD, Zukerberg L, Lees E, Arnold A, Schmidt EV . 1994 Nature 369: 669–671

  • Woodage T, King S, Wacholder S, Hartge P, Struewing J, McAdams M, Laken S, Tucker M, Brody L . 1998 Nature Genet. 20: 62–65

  • Yu Q, Geng Y, Sicinski P . 2001 Nature 411: 1017–1021

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Acknowledgements

This work was supported by the Royal Society, the BBSRC and the Association for International Cancer Research (AICR). We are grateful to Inke Nathke for the gift of the anti-APC antibody.

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Author notes

  1. Ronald C J Gallagher

    Present address: SNBTS Cell Therapy Group, John Hughes Bennett Lab, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU

Authors and Affiliations

  1. Department of Biological Sciences, Cardiff University, Cardiff CF10 3US, UK

    Trevor Hay, Valerie Meniel, Owen J Sansom & Alan R Clarke

  2. Department of Biomedical Sciences, University of Edinburgh, Medical School, Teviot Place, Edinburgh, EH8 9AG, UK

    Ronald C J Gallagher, Catherine Naughton & John O Mason

  3. Department of Pathology, University of Edinburgh, Medical School, Teviot Place, Edinburgh, EH8 9AG, UK

    Ronald C J Gallagher & Thomas J Anderson

  4. Department of Cell Biology, Cancer Institute, Toshima-ku, Tokyo, 170, Japan

    Hiroyuki Shibata, Masaki Ito & Tetsuo Noda

  5. Department of Immunology and Centre for Biomedical Genetic University Medical Center, Utrecht, The Netherlands

    Hans Clevers

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  1. Ronald C J Gallagher
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Correspondence to Alan R Clarke.

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Gallagher, R., Hay, T., Meniel, V. et al. Inactivation of Apc perturbs mammary development, but only directly results in acanthoma in the context of Tcf-1 deficiency. Oncogene 21, 6446–6457 (2002). https://doi.org/10.1038/sj.onc.1205892

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