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Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects

Abstract

Germline mutations in BRCA1 and BRCA2 are responsible for a large proportion of hereditary breast and ovarian cancers. Soon after the identification of both genes in the mid-1990s, investigators set out to develop mouse models for the associated disease. Whereas conventional Brca1 and Brca2 mouse mutants did not reveal a strong phenotype in a heterozygous setting, most homozygous mutations caused embryonic lethality. Consequently, development of mouse models for BRCA-associated tumorigenesis required the generation of tissue-specific conditional knockout animals. In this review, we give an overview of the conventional and the conditional mouse models of BRCA1 and BRCA2 deficiency generated over the last decade, as well as the contribution of these models to our understanding of the biological and molecular functions of BRCA1 and BRCA2. The most advanced mouse models for BRCA1- and BRCA2-associated tumorigenesis mimic human disease to the extent that they can be used in studies addressing clinically relevant questions. These models will help to resolve yet unanswered questions and to translate our increasing knowledge of BRCA1 and BRCA2 biology into clinical practice.

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References

  • Alberg AJ, Helzlsouer KJ . (1997). Curr Opin Oncol 9: 505–511.

  • Bachelier R, Xu X, Li C, Qiao W, Furth PA, Lubet RA et al. (2005). Oncol Rep 14: 1117–1120.

  • Bae I, Rih JK, Kim HJ, Kang HJ, Haddad B, Kirilyuk A et al. (2005). Cell Cycle 4: 1641–1666.

  • Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE et al. (1999). Science 286: 2528–2531.

  • Bennett LM, McAllister KA, Blackshear PE, Malphurs J, Goulding G, Collins NK et al. (2000). Mol Carcin 28: 174–183.

  • Berton TR, Matsumoto T, Page A, Conti CJ, Deng CX, Jorcano JL et al. (2003). Oncogene 22: 5415–5426.

  • Blackshear PE, Goldsworthy SM, Foley JF, McAllister KA, Bennett LM, Collins NK et al. (1998). Oncogene 16: 61–68.

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

  • Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E et al. (2005). Nature 434: 913–917.

  • Cao L, Kim S, Xiao C, Wang RH, Coumoul X, Wang X et al. (2006). EMBO J 25: 2167–2177.

  • Cao L, Li W, Kim S, Brodie SG, Deng CX . (2003). Genes Dev 17: 201–213.

  • Chandler J, Hohenstein P, Swing DA, Tessarollo L, Sharan SK . (2001). Genesis 29: 72–77.

  • Chappuis PO, Nethercot V, Foulkes WD . (2000). Semin Surg Oncol 18: 287–295.

  • Chen F, Nastasi A, Shen Z, Brenneman M, Crissman H, Chen DJ . (1997). Mutat Res 384: 205–211.

  • Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G et al. (1998). Mol Cell 2: 317–328.

  • Cheung AM, Elia A, Tsao MS, Done S, Wagner KU, Hennighausen L et al. (2004). Cancer Res 64: 1959–1965.

  • Cheung AM, Hande MP, Jalali F, Tsao MS, Skinnider B, Hirao A et al. (2002). Cancer Res 62: 6194–6204.

  • Collins N, McManus R, Wooster R, Mangion J, Seal S, Lakhani SR et al. (1995). Oncogene 10: 1673–1675.

  • Connor F, Bertwistle D, Mee PJ, Ross GM, Swift S, Grigorieva E et al. (1997). Nat Genet 17: 423–430.

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

  • Crook T, Crossland S, Crompton MR, Osin P, Gusterson BA . (1997). Lancet 350: 638–639.

  • Cullinane CA, Lubinski J, Neuhausen SL, Ghadirian P, Lynch HT, Isaacs C et al. (2005). Int J Cancer 117: 988–991.

  • Daniels MJ, Wang Y, Lee M, Venkitaraman AR . (2004). Science 306: 876–879.

  • de Visser KE, Eichten A, Coussens LM . (2006). Nat Rev Cancer 6: 24–37.

  • Dekker M, Brouwers C, Aarts M, van der Torre J, de Vries S, van de Vrugt H et al. (2006). Gene Therapy 13: 686–694.

  • Dekker M, Brouwers C, te Riele H . (2003). Nucleic Acids Res 31: e27.

  • Deng CX . (2006). Nucleic Acids Res 34: 1416–1426.

  • Donoho G, Brenneman MA, Cui TX, Donoviel D, Vogel H, Goodwin EH et al. (2003). Genes Chromosomes Cancer 36: 317–331.

  • Elledge SJ, Amon A . (2002). Cancer Cell 1: 129–132.

  • Elshamy WM, Livingston DM . (2004). Nat Cell Biol 6: 954–967.

  • Esashi F, Christ N, Gannon J, Liu Y, Hunt T, Jasin M et al. (2005). Nature 434: 598–604.

  • Fan S, Wang J, Yuan R, Ma Y, Meng Q, Erdos MR et al. (1999). Science 284: 1354–1356.

  • Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB et al. (2005). Nature 434: 917–921.

  • Fortin J, Moisan AM, Dumont M, Leblanc G, Labrie Y, Durocher F et al. (2005). Biochim Biophys Acta 1731: 57–65.

  • Friedman LS, Thistlethwaite FC, Patel KJ, Yu VP, Lee H, Venkitaraman AR et al. (1998). Cancer Res 58: 1338–1343.

  • Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D . (2005). Nature 437: 1043–1047.

  • Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S et al. (1994). Science 266: 120–122.

  • Ganesan S, Silver DP, Greenberg RA, Avni D, Drapkin R, Miron A et al. (2002). Cell 111: 393–405.

  • 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.

  • Hakem R, de la Pompa JL, Elia A, Potter J, Mak TW . (1997). Nat Genet 16: 298–302.

  • Hakem R, de la Pompa JL, Sirard C, Mo R, Woo M, Hakem A et al. (1996). Cell 85: 1009–1023.

  • Harkin DP, Bean JM, Miklos D, Song YH, Truong VB, Englert C et al. (1999). Cell 97: 575–586.

  • Hay T, Jenkins H, Sansom OJ, Martin NM, Smith GC, Clarke AR . (2005a). Cancer Res 65: 10145–10148.

  • Hay T, Patrick T, Winton D, Sansom OJ, Clarke AR . (2005b). Oncogene 24: 3842–3846.

  • Hohenstein P, Kielman MF, Breukel C, Bennett LM, Wiseman R, Krimpenfort P et al. (2001). Oncogene 20: 2544–2550.

  • Hollander MC, Sheikh MS, Bulavin DV, Lundgren K, Augeri-Henmueller L, Shehee R et al. (1999). Nat Genet 23: 176–184.

  • Huber LJ, Yang TW, Sarkisian CJ, Master SR, Deng CX, Chodosh LA . (2001). Mol Cell Biol 21: 4005–4015.

  • Jones LP, Li M, Halama ED, Ma Y, Lubet R, Grubbs CJ et al. (2005). Oncogene 24: 3554–3562.

  • Jonkers J, Berns A . (2002). Nat Rev Cancer 2: 251–265.

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

  • Kalluri R, Zeisberg M . (2006). Nat Rev Cancer 6: 392–401.

  • Kastan MB, Bartek J . (2004). Nature 432: 316–323.

  • Kim SS, Cao L, Li C, Xu X, Huber LJ, Chodosh LA et al. (2004). Mol Cell Biol 24: 9498–9507.

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

  • Lane TF, Deng C, Elson A, Lyu MS, Kozak CA, Leder P . (1995). Genes Dev 9: 2712–2722.

  • Lane TF . (2004). Cancer Biol Ther 3: 528–533.

  • Lee H, Trainer AH, Friedman LS, Thistlethwaite FC, Evans MJ, Ponder BA et al. (1999). Mol Cell 4: 1–10.

  • Lim DS, Hasty P . (1996). Mol Cell Biol 16: 7133–7143.

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

  • Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT et al. (2006). Mod Pathol 19: 264–271.

  • Lomonosov M, Anand S, Sangrithi M, Davies R, Venkitaraman AR . (2003). Genes Dev 17: 3017–3022.

  • Lou Z, Minter-Dykhouse K, Chen J . (2005). Nat Struct Mol Biol 12: 589–593.

  • Lu M, Conzen SD, Cole CN, Arrick BA . (1996). Cancer Res 56: 4578–4581.

  • 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.

  • Mak TW, Hakem A, McPherson JP, Shehabeldin A, Zablocki E, Migon E et al. (2000). Nat Immunol 1: 77–82.

  • Mallepell S, Krust A, Chambon P, Brisken C . (2006). Proc Natl Acad Sci USA 103: 2196–2201.

  • Marquis ST, Rajan JV, Wynshaw-Boris A, Xu J, Yin GY, Abel KJ et al. (1995). Nat Genet 11: 17–26.

  • McAllister KA, Bennett LM, Houle CD, Ward T, Malphurs J, Collins NK et al. (2002). Cancer Res 62: 990–994.

  • McPherson JP, Hande MP, Poonepalli A, Lemmers B, Zablocki E, Migon E et al. (2006). Hum Mol Genet 15: 831–838.

  • McPherson JP, Lemmers B, Hirao A, Hakem A, Abraham J, Migon E et al. (2004). Genes Dev 18: 1144–1153.

  • Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de SA, Oldenburg R et al. (2002). Nat Genet 31: 55–59.

  • Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, Warner E et al. (2004). J Clin Oncol 22: 2328–2335.

  • Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S et al. (1994). Science 266: 66–71.

  • Mixon M, Kittrell F, Medina D . (2000). Oncogene 19: 5237–5243.

  • Morimatsu M, Donoho G, Hasty P . (1998). Cancer Res 58: 3441–3447.

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

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

  • Narod SA, Foulkes WD . (2004). Nat Rev Cancer 4: 665–676.

  • Noruzinia M, Coupier I, Pujol P . (2005). Cancer 104: 1567–1574.

  • Patel KJ, Yu VP, Lee H, Corcoran A, Thistlethwaite FC, Evans MJ et al. (1998). Mol Cell 1: 347–357.

  • Pellegrini L, Venkitaraman A . (2004). Trends Biochem Sci 29: 310–316.

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

  • Rajan JV, Wang M, Marquis ST, Chodosh LA . (1996). Proc Natl Acad Sci USA 93: 13078–13083.

  • Rebbeck TR, Levin AM, Eisen A, Snyder C, Watson P, Cannon-Albright L et al. (1999). J Natl Cancer Inst 91: 1475–1479.

  • Schultz N, Lopez E, Saleh-Gohari N, Helleday T . (2003). Nucleic Acids Res 31: 4959–4964.

  • Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J et al. (1997). Cell 88: 265–275.

  • Selbert S, Bentley DJ, Melton DW, Rannie D, Lourenco P, Watson CJ et al. (1998). Transgenic Res 7: 387–396.

  • Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML et al. (2006). Nature 439: 84–88.

  • Sharan SK, Morimatsu M, Albrecht U, Lim DS, Regel E, Dinh C et al. (1997). Nature 386: 804–810.

  • Shen SX, Weaver Z, Xu X, Li C, Weinstein M, Chen L et al. (1998). Oncogene 17: 3115–3124.

  • Shin S, Verma IM . (2003). Proc Natl Acad Sci USA 100: 7201–7206.

  • Smith PD, Crossland S, Parker G, Osin P, Brooks L, Waller J et al. (1999). Oncogene 18: 2451–2459.

  • Smith SA, Easton DF, Evans DG, Ponder BA . (1992). Nat Genet 2: 128–131.

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

  • Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A et al. (2003). Proc Natl Acad Sci USA 100: 8418–8423.

  • Spillman MA, Bowcock AM . (1996). Oncogene 13: 1639–1645.

  • Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D et al. (2006). Nature 439: 993–997.

  • Suzuki A, de la Pompa JL, Hakem R, Elia A, Yoshida R, Mo R et al. (1997). Genes Dev 11: 1242–1252.

  • Tavtigian SV, Simard J, Rommens J, Couch F, Shattuck-Eidens D, Neuhausen S et al. (1996). Nat Genet 12: 333–337.

  • Thakur S, Zhang HB, Peng Y, Le H, Carroll B, Ward T et al. (1997). Mol Cell Biol 17: 444–452.

  • Turner JM, Aprelikova O, Xu X, Wang R, Kim S, Chandramouli GV et al. (2004). Curr Biol 14: 2135–2142.

  • Tutt A, Gabriel A, Bertwistle D, Connor F, Paterson H, Peacock J et al. (1999). Curr Biol 9: 1107–1110.

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

  • Venkitaraman AR . (2002). Cell 108: 171–182.

  • Wagner KU, Wall RJ, St Onge L, Gruss P, Wynshaw-Boris A, Garrett L et al. (1997). Nucleic Acids Res 25: 4323–4330.

  • Wang RH, Yu H, Deng CX . (2004a). Proc Natl Acad Sci USA 101: 17108–17113.

  • Wang X, Wang RH, Li W, Xu X, Hollander MC, Fornace Jr AJ et al. (2004b). J Biol Chem 279: 29606–29614.

  • Weaver Z, Montagna C, Xu X, Howard T, Gadina M, Brodie SG et al. (2002). Oncogene 21: 5097–5107.

  • Wilson CA, Payton MN, Elliott GS, Buaas FW, Cajulis EE, Grosshans D et al. (1997). Oncogene 14: 1–16.

  • Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J et al. (1995). Nature 378: 789–792.

  • Xia F, Taghian DG, DeFrank JS, Zeng ZC, Willers H, Iliakis G et al. (2001). Proc Natl Acad Sci USA 98: 8644–8649.

  • Xu CF, Chambers JA, Nicolai H, Brown MA, Hujeirat Y, Mohammed S et al. (1997). Genes Chromosomes Cancer 18: 102–110.

  • Xu J, Fan S, Rosen EM . (2005). Endocrinology 146: 2031–2047.

  • Xu X, Qiao W, Linke SP, Cao L, Li WM, Furth PA et al. (2001). Nat Genet 28: 266–271.

  • Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T et al. (1999a). Nat Genet 22: 37–43.

  • Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW et al. (1999b). Mol Cell 3: 389–395.

  • Yan DH, Wen Y, Su LK, Xia W, Wang SC, Zhang S et al. (2004). Oncogene 23: 1896–1901.

  • Yang Y, Swaminathan S, Martin BK, Sharan SK . (2003). Hum Mol Genet 12: 2121–2131.

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Acknowledgements

We thank Peter Bouwman, Rinske Drost, Xiaoling Liu and Karin de Visser for critical reading the manuscript and providing helpful suggestions. BE is supported by a grant from the Netherlands Organization for Scientific Research (NWO-VIDI 917.36.347).

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Evers, B., Jonkers, J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene 25, 5885–5897 (2006). https://doi.org/10.1038/sj.onc.1209871

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