Advertisement

Studying Therapy Response and Resistance in Mouse Models for BRCA1-Deficient Breast Cancer

  • Ewa Malgorzata Michalak
  • Jos Jonkers
Article

Abstract

Worldwide, more than one million women are diagnosed with breast cancer every year, making it the most common malignancy of females in the developed world. Germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 account for 4–6% of all breast cancer cases, and mutation carriers have a lifetime risk of 80% for developing breast cancer and 40% for developing ovarian cancer. Current treatment options are limited and often do not lead to cure. In the 17 years since the discovery of BRCA1, the generation of mouse models for BRCA1 deficiency has greatly aided our understanding of it’s role in tumorigenesis. In contrast to human BRCA1 mutation carriers, mice carrying heterozygous mutations in Brca1 did not develop spontaneous tumors. This led to the generation of conditional mouse models in which tissue-specific Brca1 deletion induces formation of mammary tumors that closely resemble human BRCA1-mutated breast tumors. These models have proven useful for studying BRCA1-related tumor development, drug response and resistance. BRCA1-deficient cancer cells are defective in DNA repair mediated by homologous recombination (HR) and therefore highly sensitive to DNA-damaging agents such as platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors. However, BRCA1-mutated tumors can develop resistance to these drugs; hence improved treatment strategies are critical. Existing mouse models have already proven useful for preclinical testing of (combinations of) therapeutic agents that may be beneficial for the treatment of patients with BRCA1-mutated tumors. In this review, we discuss the progress made towards modeling BRCA1-deficient breast cancer in mice and what we have learned from preclinical studies using these models.

Keywords

BRCA1 Genetically engineered mouse models PARP inhibitors Platinum drugs Therapy resistance 

Abbreviations

aCGH

array comparative genomic hybridization

BRCA1

breast cancer susceptibility gene 1

BRCA2

breast cancer susceptibility gene 2

CNA

copy number alteration

DDR

DNA damage response

DSBs

double-strand breaks

ER

estrogen receptor

ESC

embryonic stem cell

GEM

genetically engineered mouse

HER2

human epidermal growth factor receptor 2

HR

homologous recombination

MaSCs

mammary stem cells

PARP

poly(ADP-ribose) polymerase

P-gp

P-glycoprotein

PR

progesterone receptor

TIC

tumor initiating cell

TNBC

triple negative breast cancer.

Notes

Acknowledgements

We thank Drs. Karin de Visser and Jonathan Coquet for critical reading of the manuscript. This work is financially supported by grants from the European Commission (FP7 project EuroSyStem), the Dutch Cancer Society (grants NKI 2007–3772 and NKI 2008–4116) and the Center for Translation Molecular medicine (Breast CaRe). E.M was supported by fellowships from the European Commission (Marie Curie fellowship PIIF-GA-2009-237486) and the National Health and Medical Research Council Australia (#575577).

References

  1. 1.
    Herschkowitz JI, Simin K, Weigman VJ, Mikaelian I, Usary J, Hu Z, et al. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. 2007;8(5):R76.PubMedCrossRefGoogle Scholar
  2. 2.
    Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.PubMedCrossRefGoogle Scholar
  3. 3.
    Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363(20):1938–48.Google Scholar
  4. 4.
    Turner N, Tutt A, Ashworth A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer. 2004;4(10):814–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Ferla R, Calo V, Cascio S, Rinaldi G, Badalamenti G, Carreca I, et al. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007;18 Suppl 6:vi93–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Linger RJ, Kruk PA. BRCA1 16 years later: risk-associated BRCA1 mutations and their functional implications. FEBS J. 2010;277(15):3086–96.Google Scholar
  7. 7.
    Easton DF, Deffenbaugh AM, Pruss D, Frye C, Wenstrup RJ, Allen-Brady K, et al. A systematic genetic assessment of 1, 433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007;81(5):873–83.PubMedCrossRefGoogle Scholar
  8. 8.
    Huen MS, Sy SM, Chen J. BRCA1 and its toolbox for the maintenance of genome integrity. Nat Rev Mol Cell Biol. 2010;11(2):138–48.Google Scholar
  9. 9.
    Mullan PB, Quinn JE, Harkin DP. The role of BRCA1 in transcriptional regulation and cell cycle control. Oncogene. 2006;25(43):5854–63.PubMedCrossRefGoogle Scholar
  10. 10.
    Ganesan S, Silver DP, Greenberg RA, Avni D, Drapkin R, Miron A, et al. BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell. 2002;111(3):393–405.PubMedCrossRefGoogle Scholar
  11. 11.
    Gowen LC, Johnson BL, Latour AM, Sulik KK, Koller BH. Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat Genet. 1996;12(2):191–4.PubMedCrossRefGoogle Scholar
  12. 12.
    Hakem R, de la Pompa JL, Sirard C, Mo R, Woo M, Hakem A, et al. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell. 1996;85(7):1009–23.PubMedCrossRefGoogle Scholar
  13. 13.
    Liu CY, Flesken-Nikitin A, Li S, Zeng Y, Lee WH. Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. Genes Dev. 1996;10(14):1835–43.PubMedCrossRefGoogle Scholar
  14. 14.
    Smith SA, Easton DF, Evans DG, Ponder BA. Allele losses in the region 17q12-21 in familial breast and ovarian cancer involve the wild-type chromosome. Nat Genet. 1992;2(2):128–31.PubMedCrossRefGoogle Scholar
  15. 15.
    Holstege H, Joosse SA, van Oostrom CT, Nederlof PM, de Vries A, Jonkers J. High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. Cancer Res. 2009;69(8):3625–33.PubMedCrossRefGoogle Scholar
  16. 16.
    Manie E, Vincent-Salomon A, Lehmann-Che J, Pierron G, Turpin E, Warcoin M, et al. High frequency of TP53 mutation in BRCA1 and sporadic basal-like carcinomas but not in BRCA1 luminal breast tumors. Cancer Res. 2009;69(2):663–71.PubMedCrossRefGoogle Scholar
  17. 17.
    Joosse SA, van Beers EH, Tielen IH, Horlings H, Peterse JL, Hoogerbrugge N, et al. Prediction of BRCA1-association in hereditary non-BRCA1/2 breast carcinomas with array-CGH. Breast Cancer Res Treat. 2009;116(3):479–89.PubMedCrossRefGoogle Scholar
  18. 18.
    Wessels LF, van Welsem T, Hart AA, van’t Veer LJ, Reinders MJ, Nederlof PM. Molecular classification of breast carcinomas by comparative genomic hybridization: a specific somatic genetic profile for BRCA1 tumors. Cancer Res. 2002;62(23):7110–7.PubMedGoogle Scholar
  19. 19.
    Vollebergh MA, Lips EH, Nederlof PM, Wessels LF, Schmidt MK, van Beers EH, et al. An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients. Ann Oncol. 2010 Dec 6. [Epub ahead of print]Google Scholar
  20. 20.
    Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 2000;92(7):564–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Turner NC, Reis-Filho JS, Russell AM, Springall RJ, Ryder K, Steele D, et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene. 2007;26(14):2126–32.PubMedCrossRefGoogle Scholar
  22. 22.
    Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005;11(16):5678–85.PubMedCrossRefGoogle Scholar
  23. 23.
    Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15 Pt 1):4429–34.PubMedCrossRefGoogle Scholar
  25. 25.
    Kassam F, Enright K, Dent R, Dranitsaris G, Myers J, Flynn C, et al. Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin Breast Cancer. 2009;9(1):29–33.PubMedCrossRefGoogle Scholar
  26. 26.
    Moynahan ME, Cui TY, Jasin M. Homology-directed dna repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res. 2001;61(12):4842–50.PubMedGoogle Scholar
  27. 27.
    Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol. 2008;26(22):3785–90.PubMedCrossRefGoogle Scholar
  28. 28.
    Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007;7(8):573–84.PubMedCrossRefGoogle Scholar
  29. 29.
    Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, et al. Efficacy of neoadjuvant Cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28(7):1145–53.Google Scholar
  30. 30.
    Byrski T, Gronwald J, Huzarski T, Grzybowska E, Budryk M, Stawicka M, et al. Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol. 2010;28(3):375–9.Google Scholar
  31. 31.
    Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21.PubMedCrossRefGoogle Scholar
  33. 33.
    Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34.PubMedCrossRefGoogle Scholar
  34. 34.
    Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010;28(15):2512–9.Google Scholar
  35. 35.
    Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376(9737):245–51.Google Scholar
  36. 36.
    Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235–44.Google Scholar
  37. 37.
    Veeck J, Ropero S, Setien F, Gonzalez-Suarez E, Osorio A, Benitez J, et al. BRCA1 CpG island hypermethylation predicts sensitivity to poly(adenosine diphosphate)-ribose polymerase inhibitors. J Clin Oncol. 2010;28(29):e563–4; author reply e565–6.Google Scholar
  38. 38.
    O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C, et al. Iniparib plus Chemotherapy in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2011;364(3):205-14.Google Scholar
  39. 39.
    Pal SK, Childs BH, Pegram M. Triple negative breast cancer: unmet medical needs. Breast Cancer Res Treat. 2011;125(3):627-36.Google Scholar
  40. 40.
    Santana-Davila R, Perez EA. Treatment options for patients with triple-negative breast cancer. J Hematol Oncol. 2010;3:42.Google Scholar
  41. 41.
    Sharpless NE, Depinho RA. The mighty mouse: genetically engineered mouse models in cancer drug development. Nat Rev Drug Discov. 2006;5(9):741–54.PubMedCrossRefGoogle Scholar
  42. 42.
    Peeper D, Berns A. Cross-species oncogenomics in cancer gene identification. Cell. 2006;125(7):1230–3.PubMedCrossRefGoogle Scholar
  43. 43.
    Lim E, Wu D, Pal B, Bouras T, Asselin-Labat ML, Vaillant F, et al. Transcriptome analyses of mouse and human mammary cell subpopulations reveal multiple conserved genes and pathways. Breast Cancer Res. 2010;12(2):R21.Google Scholar
  44. 44.
    Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3(8):711–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Wu M, Jung L, Cooper AB, Fleet C, Chen L, Breault L, et al. Dissecting genetic requirements of human breast tumorigenesis in a tissue transgenic model of human breast cancer in mice. Proc Natl Acad Sci USA. 2009;106(17):7022–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Garber K. From human to mouse and back: ‘tumorgraft’ models surge in popularity. J Natl Cancer Inst. 2009;101(1):6–8.PubMedGoogle Scholar
  47. 47.
    Marangoni E, Vincent-Salomon A, Auger N, Degeorges A, Assayag F, de Cremoux P, et al. A new model of patient tumor-derived breast cancer xenografts for preclinical assays. Clin Cancer Res. 2007;13(13):3989–98.PubMedCrossRefGoogle Scholar
  48. 48.
    de Plater L, Lauge A, Guyader C, Poupon MF, Assayag F, de Cremoux P, et al. Establishment and characterisation of a new breast cancer xenograft obtained from a woman carrying a germline BRCA2 mutation. Br J Cancer. 2010;103(8):1192–200.Google Scholar
  49. 49.
    Drost RM, Jonkers J. Preclinical mouse models for BRCA1-associated breast cancer. Br J Cancer. 2009;101(10):1651–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Evers B, Jonkers J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene. 2006;25(43):5885–97.PubMedCrossRefGoogle Scholar
  51. 51.
    Ludwig T, Chapman DL, Papaioannou VE, Efstratiadis A. 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. 1997;11(10):1226–41.PubMedCrossRefGoogle Scholar
  52. 52.
    Liu X, Holstege H, van der Gulden H, Treur-Mulder M, Zevenhoven J, Velds A, et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci USA. 2007;104(29):12111–6.PubMedCrossRefGoogle Scholar
  53. 53.
    McCarthy A, Savage K, Gabriel A, Naceur C, Reis-Filho JS, Ashworth A. A mouse model of basal-like breast carcinoma with metaplastic elements. J Pathol. 2007;211(4):389–98.PubMedCrossRefGoogle Scholar
  54. 54.
    Xu X, Qiao W, Linke SP, Cao L, Li WM, Furth PA, et al. Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet. 2001;28(3):266–71.PubMedCrossRefGoogle Scholar
  55. 55.
    Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H, Natrajan R, et al. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell. 2010;7(3):403–17.Google Scholar
  56. 56.
    Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW, et al. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell. 1999;3(3):389–95.PubMedCrossRefGoogle Scholar
  57. 57.
    Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, et al. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med. 2009;15(8):907–13.PubMedCrossRefGoogle Scholar
  58. 58.
    Holstege H, van Beers E, Velds A, Liu X, Joosse SA, Klarenbeek S, et al. Cross-species comparison of aCGH data from mouse and human BRCA1- and BRCA2-mutated breast cancers. BMC Cancer. 2010;10:455.Google Scholar
  59. 59.
    Chetrit A, Hirsh-Yechezkel G, Ben-David Y, Lubin F, Friedman E, Sadetzki S. Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer. J Clin Oncol. 2008;26(1):20–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Satagopan JM, Offit K, Foulkes W, Robson ME, Wacholder S, Eng CM, et al. The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev. 2001;10(5):467–73.Google Scholar
  61. 61.
    Ben David Y, Chetrit A, Hirsh-Yechezkel G, Friedman E, Beck BD, Beller U, et al. Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol. 2002;20(2):463–6.PubMedCrossRefGoogle Scholar
  62. 62.
    Saal LH, Gruvberger-Saal SK, Persson C, Lovgren K, Jumppanen M, Staaf J, et al. Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nat Genet. 2008;40(1):102–7.PubMedCrossRefGoogle Scholar
  63. 63.
    Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA. 2003;100(20):11606–11.PubMedCrossRefGoogle Scholar
  64. 64.
    Pietersen AM, Horlings HM, Hauptmann M, Langerod A, Ajouaou A, Cornelissen-Steijger P, et al. EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer. Breast Cancer Res. 2008;10(6):R109.PubMedCrossRefGoogle Scholar
  65. 65.
    Puppe J, Drost R, Liu X, Joosse SA, Evers B, Cornelissen-Steijger P, et al. BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A. Breast Cancer Res. 2009;11(4):R63.PubMedCrossRefGoogle Scholar
  66. 66.
    Ying QL, Wray J, Nichols J, Batlle-Morera L, Doble B, Woodgett J, et al. The ground state of embryonic stem cell self-renewal. Nature. 2008;453(7194):519–23.PubMedCrossRefGoogle Scholar
  67. 67.
    Nichols J, Jones K, Phillips JM, Newland SA, Roode M, Mansfield W, et al. Validated germline-competent embryonic stem cell lines from nonobese diabetic mice. Nat Med. 2009;15(7):814–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Narod SA, Offit K. Prevention and management of hereditary breast cancer. J Clin Oncol. 2005;23(8):1656–63.PubMedCrossRefGoogle Scholar
  69. 69.
    Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL, van ’t Veer L, Garber JE, et al. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2004;22(6):1055–62.PubMedCrossRefGoogle Scholar
  70. 70.
    Asselin-Labat ML, Vaillant F, Sheridan JM, Pal B, Wu D, Simpson ER, et al. Control of mammary stem cell function by steroid hormone signalling. Nature. 2010;465(7299):798–802.Google Scholar
  71. 71.
    Joshi PA, Jackson HW, Beristain AG, Di Grappa MA, Mote PA, Clarke CL, et al. Progesterone induces adult mammary stem cell expansion. Nature. 465(7299):803–7.Google Scholar
  72. 72.
    Poole AJ, Li Y, Kim Y, Lin SC, Lee WH, Lee EY. Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist. Science. 2006;314(5804):1467–70.PubMedCrossRefGoogle Scholar
  73. 73.
    Rottenberg S, Pajic M, Jonkers J. Studying drug resistance using genetically engineered mouse models for breast cancer. Methods Mol Biol. 2010;596:33–45.Google Scholar
  74. 74.
    Evers B, Drost R, Schut E, de Bruin M, van der Burg E, Derksen PW, et al. Selective Inhibition of BRCA2-Deficient Mammary Tumor Cell Growth by AZD2281 and Cisplatin. Clin Cancer Res. 2008;14(12):3916–25.PubMedCrossRefGoogle Scholar
  75. 75.
    Kortmann UK, McAlpine JN, Xue H, Guan J, Ha G, Tully S, et al. Tumor growth inhibition by olaparib in BRCA2 germline-mutated patient-derived ovarian cancer tissue xenografts. Clin Cancer Res.Google Scholar
  76. 76.
    Rottenberg S, Nygren AO, Pajic M, van Leeuwen FW, van der Heijden I, van de Wetering K, et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc Natl Acad Sci USA. 2007;104(29):12117–22.PubMedCrossRefGoogle Scholar
  77. 77.
    Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci USA. 2008;105(44):17079–84.PubMedCrossRefGoogle Scholar
  78. 78.
    Zander SA, Kersbergen A, van der Burg E, de Water N, van Tellingen O, Gunnarsdottir S, et al. Sensitivity and acquired resistance of BRCA1;p53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan. Cancer Res. 2010;70(4):1700–10.Google Scholar
  79. 79.
    Evers B, Schut E, van der Burg E, Braumuller TM, Egan DA, Holstege H, et al. A high-throughput pharmaceutical screen identifies compounds with specific toxicity against BRCA2-deficient tumors. Clin Cancer Res. 2010;16(1):99–108.Google Scholar
  80. 80.
    Huang F, Kushner YB, Langleben A, Foulkes WD. Eleven years disease-free: role of chemotherapy in metastatic BRCA2-related breast cancer. Nat Rev Clin Oncol. 2009;6(8):488–92.PubMedCrossRefGoogle Scholar
  81. 81.
    Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature. 2008;451(7182):1111–5.PubMedCrossRefGoogle Scholar
  82. 82.
    Swisher EM, Sakai W, Karlan BY, Wurz K, Urban N, Taniguchi T. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 2008;68(8):2581–6.PubMedCrossRefGoogle Scholar
  83. 83.
    Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008;451(7182):1116–20.PubMedCrossRefGoogle Scholar
  84. 84.
    Jaspers JE, Rottenberg S, Jonkers J. Therapeutic options for triple-negative breast cancers with defective homologous recombination. Biochim Biophys Acta. 2009;1796(2):266–80.PubMedGoogle Scholar
  85. 85.
    Ishida S, McCormick F, Smith-McCune K, Hanahan D. Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator. Cancer Cell. 2010;17(6):574–83.Google Scholar
  86. 86.
    Shafee N, Smith CR, Wei S, Kim Y, Mills GB, Hortobagyi GN, et al. Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors. Cancer Res. 2008;68(9):3243–50.PubMedCrossRefGoogle Scholar
  87. 87.
    Hakem R, de la Pompa JL, Elia A, Potter J, Mak TW. Partial rescue of Brca1 (5–6) early embryonic lethality by p53 or p21 null mutation. Nat Genet. 1997;16(3):298–302.PubMedCrossRefGoogle Scholar
  88. 88.
    Cao L, Xu X, Bunting SF, Liu J, Wang RH, Cao LL, et al. A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol Cell. 2009;35(4):534–41.PubMedCrossRefGoogle Scholar
  89. 89.
    Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der Gulden H, et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol. 2010;17(6):688–95.Google Scholar
  90. 90.
    Bunting SF, Callen E, Wong N, Chen HT, Polato F, Gunn A, et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell. 2010;141(2):243–54.Google Scholar
  91. 91.
    Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, et al. Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006;66(19):9339–44.PubMedCrossRefGoogle Scholar
  92. 92.
    Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.PubMedCrossRefGoogle Scholar
  93. 93.
    Pajic M, Kersbergen A, van Diepen F, Pfauth A, Jonkers J, Borst P, et al. Tumor-initiating cells are not enriched in cisplatin-surviving BRCA1;p53-deficient mammary tumor cells in vivo. Cell Cycle. 2010;9(18):3780–91.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of Molecular BiologyNetherlands Cancer InstituteAmsterdamThe Netherlands

Personalised recommendations