Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans

Oncogene volume 21, pages 8994–9007 (2002)Cite this article

Abstract

BRCA1 and BRCA2 mutations are estimated to be responsible for the great majority of familial breast and ovarian cancers. Much progress has been made toward the understanding of the function of these proteins through genetic, biochemical, and structural studies. The embryonic lethality encountered in the knockout mouse initially hindered the development of mouse models aimed at studying tumor suppression. However, mice that harbor hypomorphic Brca1 and Brca2 alleles and cre-mediated tissue-specific deletions for Brca1 and Brca2 have been generated. Mice deficient for either Brca1 or Brca2 sustain a wide range of carcinoma and mammary epithelium deleted for Brca1 or Brca2 is highly susceptible to mammary tumorigenesis. Mammary (and other) tumors occur at long latency as compared to oncogene-induced mouse tumors. p53 deficiency is highly cooperative with both Brca1 and Brca2 in promoting tumorigenesis. Analysis of Brca1-associated mammary tumors reveals significant similarities to BRCA1-associated breast cancer in regard to high tumor grade, hormone receptor negativity, a high incidence of p53 mutations and genetic instability.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  • Baer R, Ludwig T . 2002 Curr. Opin. Genet. Dev. 12: 86–91

  • Basham VM, Lipscombe JM, Ward JM, Gayther SA, Ponder BA, Easton DF, Pharoah PD . 2002 Breast Cancer Res. 4: R2

  • Breast Cancer Linkage Consortium. 1999 J. Natl. Cancer Inst. 91: 1310–1316

  • Begg CB . 2002 J. Natl. Cancer Inst. 94: 1221–1226

  • Bennett LM, McAllister KA, Blackshear PE, Malphurs J, Goulding G, Collins NK, Ward T, Bunch DO, Eddy EM, Davis BJ, Wiseman RW . 2000a Mol. Carcinog. 28: 174–183

  • Bennett LM, McAllister KA, Malphurs J, Ward T, Collins NK, Seely JC, Gowen LC, Koller BH, Davis BJ, Wiseman RW . 2000b Cancer Res. 60: 3461–3469

  • Bennett LM, McAllister KA, Ward T, Malphurs J, Collins NK, Seely JC, Davis BJ, Wiseman RW . 2001 Toxicol. Pathol. 29: 117–125

  • Brodie SG, Xu X, Qiao W, Li WM, Cao L, Deng CX . 2001 Oncogene 20: 7514–7523

  • Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL . 2002 J. Natl. Cancer Inst. 94: 1365–1372

  • Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R . 1998 Mol. Cell 2: 317–328

  • Connor F, Bertwistle D, Mee PJ, Ross GM, Swift S, Grigorieva E, Tybulewicz VL, Ashworth A . 1997 Nat. Genet. 17: 423–430

  • Cortez D, Wang Y, Qin J, Elledge SJ . 1999 Science 286: 1162–1166

  • Cressman VL, Backlund DC, Avrutskaya AV, Leadon SA, Godfrey V, Koller BH . 1999a Mol. Cell. Biol. 19: 7061–7075

  • Cressman VL, Backlund DC, Hicks EM, Gowen LC, Godfrey V, Koller BH . 1999b Cell Growth Differ. 10: 1–10

  • 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, Gusterson BA . 1998 Oncogene 17: 1681–1689

  • Davies AA, Masson JY, McIlwraith MJ, Stasiak AZ, Stasiak A, Venkitaraman AR, West SC . 2001 Mol. Cell 7: 273–282

  • Deng CX . 2002 Oncogene 21: 6222–6227

  • Deng CX, Brodie SG . 2001 Semin. Cancer Biol. 11: 387–394

  • Easton DF, Bishop DT, Ford D, Crockford GP . 1993 Am. J. Hum. Genet. 52: 678–701

  • Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE, Lingenfelter B, Gumpper KL, Scholl T, Tavtigian SV, Pruss DR, Critchfield GC . 2002 J. Clin. Oncol. 20: 1480–1490

  • Friedman LS, Thistlethwaite FC, Patel KJ, Yu VP, Lee H, Venkitaraman AR, Abel KJ, Carlton MB, Hunter SM, Colledge WH, Evans MJ, Ponder BA . 1998 Cancer Res. 58: 1338–1343

  • Gowen LC, Johnson BL, Latour AM, Sulik KK, Koller BH . 1996 Nat. Genet. 12: 191–194

  • Greenblatt MS, Chappuis PO, Bond JP, Hamel N, Foulkes WD . 2001 Cancer Res. 61: 4092–4097

  • Gruber SB, Petersen GM . 2002 J. Natl. Cancer Inst. 94: 1344–1345

  • Hakem R, de la Pompa JL, Sirard C, Mo R, Woo M, Hakem A, Wakeham A, Potter J, Reitmair A, Billia F, Firpo E, Hui CC, Roberts J, Rossant J, Mak TW . 1996 Cell 85: 1009–1023

  • Hakem R, Mak TW . 2001 Annu. Rev. Genet. 35: 209–241

  • Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King MC . 1990 Science 250: 1684–1689

  • Hedenfalk I, Duggan D, Chen Y, Radmacher M, Bittner M, Simon R, Meltzer P, Gusterson B, Esteller M, Kallioniemi OP, Wilfond B, Borg A, Trent J . 2001 N. Engl. J. Med. 344: 539–548

  • Hohenstein P, Kielman MF, Breukel C, Bennett LM, Wiseman R, Krimpenfort P, Cornelisse C, van Ommen GJ, Devilee P, Fodde R . 2001 Oncogene 20: 2544–2550

  • Janocko LE, Brown KA, Smith CA, Gu LP, Pollice AA, Singh SG, Julian T, Wolmark N, Sweeney L, Silverman JF, Shackney SE . 2001 Cytometry 46: 136–149

  • Jazaeri AA, Yee CJ, Sotiriou C, Brantley KR, Boyd J, Liu ET . 2002 J. Natl. Cancer Inst. 94: 990–1000

  • Jones C, Nonni AV, Fulford L, Merrett S, Chaggar R, Eusebi V, Lakhani SR . 2001 Br. J. Cancer 85: 422–427

  • Jonkers J, Meuwissen R, van der Gulden H, Peterse H, van der Valk M, Berns A . 2001 Nat. Genet. 29: 418–425

  • Karabinis ME, Larson D, Barlow C, Wynshaw-Boris A, Moser AR . 2001 Carcinogenesis 22: 343–346

  • Kuperwasser C, Hurlbut GD, Kittrell FS, Dickinson ES, Laucirica R, Medina D, Naber SP, Jerry DJ . 2000 Am. J. Pathol. 157: 2151–2159

  • Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, Easton DF . 2002 J. Clin. Oncol. 20: 2310–2318

  • Lee JS, Collins KM, Brown AL, Lee CH, Chung JH . 2000 Nature 404: 201–204

  • Levy-Lahad E, Lahad A, Eisenberg S, Dagan E, Paperna T, Kasinetz L, Catane R, Kaufman B, Beller U, Renbaum P, Gershoni-Baruch R . 2001 Proc. Natl. Acad. Sci. USA 98: 3232–3236

  • Liu CY, Flesken-Nikitin A, Li S, Zeng Y, Lee WH . 1996 Genes Dev. 10: 1835–1843

  • Ludwig T, Chapman DL, Papaioannou VE, Efstratiadis A . 1997 Genes Dev. 11: 1226–1241

  • Ludwig T, Fisher P, Ganesan S, Efstratiadis A . 2001a Genes Dev. 15: 1188–1193

  • Ludwig T, Fisher P, Murty V, Efstratiadis A . 2001b Oncogene 20: 3937–3948

  • MacLachlan TK, Takimoto R, El-Deiry WS . 2002 Mol. Cell. Biol. 22: 4280–4292

  • Mak TW, Hakem A, McPherson JP, Shehabeldin A, Zablocki E, Migon E, Duncan GS, Bouchard D, Wakeham A, Cheung A, Karaskova J, Sarosi I, Squire J, Marth J, Hakem R . 2000 Nat. Immunol. 1: 77–82

  • McAllister KA, Bennett LM, Houle CD, Ward T, Malphurs J, Collins NK, Cachafeiro C, Haseman J, Goulding EH, Bunch D, Eddy EM, Davis BJ, Wiseman RW . 2002 Cancer Res. 62: 990–994

  • Medina D, Ullrich R, Meyn R, Wiseman R, Donehower L . 2002 Environ. Mol. Mutagen. 39: 178–183

  • Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W et al . 1994 Science 266: 66–71

  • Monteiro AN . 2002 Cancer Biol. Ther. 1: 187–188

  • Moynahan ME, Chiu JW, Koller BH, Jasin M . 1999 Mol. Cell 4: 511–518

  • Moynahan ME, Cui TY, Jasin M . 2001a Cancer Res. 61: 4842–4850

  • Moynahan ME, Pierce AJ, Jasin M . 2001b Mol. Cell 7: 263–272

  • Phillips KA . 2000 J. Clin. Oncol. 18: 107S–112S

  • Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, Jack E, Vesprini DJ, Kuperstein G, Abrahamson JL, Fan I, Wong B, Narod SA . 2001 Am. J. Hum. Genet. 68: 700–710

  • Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM . 1997 Cell 88: 265–275

  • Seidman AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, Panageas KS, Arroyo C, Valero V, Currie V, Gilewski T, Theodoulou M, Moynahan ME, Moasser M, Sklarin N, Dickler M, D'Andrea G, Cristofanilli M, Rivera E, Hortobagyi GN, Norton L, Hudis CA . 2001 J. Clin. Oncol. 19: 2587–2595

  • Sharan SK, Morimatsu M, Albrecht U, Lim DS, Regel E, Dinh C, Sands A, Eichele G, Hasty P, Bradley A . 1997 Nature 386: 804–810

  • Shen SX, Weaver Z, Xu X, Li C, Weinstein M, Chen L, Guan XY, Ried T, Deng CX . 1998 Oncogene 17: 3115–3124

  • Shin SJ, Rosen PP . 2002 Am. J. Surg. Pathol. 26: 413–420

  • Smith PD, Crossland S, Parker G, Osin P, Brooks L, Waller J, Philp E, Crompton MR, Gusterson BA, Allday MJ, Crook T . 1999 Oncogene 18: 2451–2459

  • Thompson D, Easton DF . 2002 J. Natl. Cancer Inst. 94: 1358–1365

  • Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT . 2000 Genes Dev. 14: 2989–3002

  • Turner BC, Ottey M, Zimonjic DB, Potoczek M, Hauck WW, Pequignot E, Keck-Waggoner CL, Sevignani C, Aldaz CM, McCue PA, Palazzo J, Huebner K, Popescu NC . 2002 Cancer Res. 62: 4054–4060

  • Tutt A, Gabriel A, Bertwistle D, Connor F, Paterson H, Peacock J, Ross G, Ashworth A . 1999 Curr. Biol. 9: 1107–1110

  • Tutt AN, van Oostrom CT, Ross GM, van Steeg H, Ashworth A . 2002 EMBO Rep. 3: 255–260

  • van't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH . 2002 Nature 415: 530–536

  • Wang WW, Spurdle AB, Kolachana P, Bove B, Modan B, Ebbers SM, Suthers G, Tucker MA, Kaufman DJ, Doody MM, Tarone RE, Daly M, Levavi H, Pierce H, Chetrit A, Yechezkel GH, Chenevix-Trench G, Offit K, Godwin AK, Struewing JP . 2001 Cancer Epidemiol. Biomarkers Prev. 10: 955–960

  • Weaver Z, Montagna C, Xu X, Howard T, Gadina M, Brodie SG, Deng CX, Ried T . 2002 Oncogene 21: 5097–5107

  • Welcsh PL, King MC . 2001 Hum. Mol. Genet. 10: 705–713

  • Welcsh PL, Lee MK, Gonzalez-Hernandez RM, Black DJ, Mahadevappa M, Swisher EM, Warrington JA, King MC . 2002 Proc. Natl. Acad. Sci. USA 99: 7560–7565

  • Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D et al . 1994 Science 265: 2088–2090

  • Xu B, Kim S, Kastan MB . 2001a Mol. Cell. Biol. 21: 3445–3450

  • Xu X, Qiao W, Linke SP, Cao L, Li WM, Furth PA, Harris CC, Deng CX . 2001b Nat. Genet. 28: 266–271

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

  • Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW, Harris CC, Ried T, Deng CX . 1999b Mol. Cell 3: 389–395

  • Yang H, Jeffrey PD, Miller J, Kinnucan E, Sun Y, Thoma NH, Zheng N, Chen PL, Lee WH, Pavletich NP . 2002 Science 297: 1837–1848

  • Yarden RI, Pardo-Reoyo S, Sgagias M, Cowan KH, Brody LC . 2002 Nat. Genet. 30: 285–289

  • Yu VP, Koehler M, Steinlein C, Schmid M, Hanakahi LA, van Gool AJ, West SC, Venkitaraman AR . 2000 Genes Dev. 14: 1400–1406

Download references

Acknowledgements

I would like to thank Larry Norton and the Breast Cancer Research Fund for support and Maria Jasin and Mark Robson for helpful comments and review of the manuscript.

Author information

Authors and Affiliations

  1. Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, NY, USA

    Mary Ellen Moynahan

Authors
  1. Mary Ellen Moynahan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mary Ellen Moynahan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Moynahan, M. The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans. Oncogene 21, 8994–9007 (2002). https://doi.org/10.1038/sj.onc.1206177

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206177

Keywords

This article is cited by

Search

Advanced search

Quick links