Breast Cancer Research and Treatment

, Volume 113, Issue 2, pp 285–291

Deleterious CHEK2 1100delC and L303X mutants identified among 38 human breast cancer cell lines

  • Marijke Wasielewski
  • Pejman Hanifi-Moghaddam
  • Antoinette Hollestelle
  • Sofia D. Merajver
  • Ans van den Ouweland
  • Jan G. M. Klijn
  • Stephen P. Ethier
  • Mieke Schutte
Preclinical Study


The CHEK2 protein plays a major role in the regulation of DNA damage response pathways. Mutations in the CHEK2 gene, in particular 1100delC, have been associated with increased cancer risks, but the precise function of CHEK2 mutations in carcinogenesis is not known. Human cancer cell lines with CHEK2 mutations are therefore of main interest. Here, we have sequenced 38 breast cancer cell lines for mutations in the CHEK2 gene and identified two cell lines with deleterious CHEK2 mutations. Cell line UACC812 has a nonsense truncating mutation in the CHEK2 kinase domain (L303X) and cell line SUM102PT has the well-known oncogenic CHEK2 1100delC founder mutation. Immunohistochemical analysis revealed that the two CHEK2 mutant cell lines expressed neither CHEK2 nor P-Thr68 CHEK2 proteins, implying abrogation of normal CHEK2 DNA repair functions. Cell lines UACC812 and SUM102PT thus are the first human CHEK2 null cell lines reported and should therefore be a major help in further unraveling the function of CHEK2 mutations in carcinogenesis.


Cancer susceptibility Cell lines Gene mutation CHK2 p53 


  1. 1.
    Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3:421–429PubMedCrossRefGoogle Scholar
  2. 2.
    Ahn J, Urist M, Prives C (2004) The Chk2 protein kinase. DNA Repair (Amst) 3:1039–1047CrossRefGoogle Scholar
  3. 3.
    Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439PubMedCrossRefGoogle Scholar
  4. 4.
    Meijers-Heijboer H, van den Ouweland A, Klijn J et al (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31:55–59PubMedCrossRefGoogle Scholar
  5. 5.
    Vahteristo P, Bartkova J, Eerola H et al (2002) A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71:432–438PubMedCrossRefGoogle Scholar
  6. 6.
    Nevanlinna H, Bartek J (2006) The CHEK2 gene and inherited breast cancer susceptibility. Oncogene 25:5912–5919PubMedCrossRefGoogle Scholar
  7. 7.
    Wasielewski M, Elstrodt F, Klijn JG, Berns EM, Schutte M (2006) Thirteen new p53 gene mutants identified among 41 human breast cancer cell lines. Breast Cancer Res Treat 99:97–101PubMedCrossRefGoogle Scholar
  8. 8.
    Chen TR, Dorotinsky CS, McGuire LJ, Macy ML, Hay RJ (1995) DLD-1 and HCT-15 cell lines derived separately from colorectal carcinomas have totally different chromosome changes but the same genetic origin. Cancer Genet Cytogenet 81:103–108PubMedCrossRefGoogle Scholar
  9. 9.
    Elstrodt F, Hollestelle A, Nagel JH et al (2006) BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants. Cancer Res 66:41–45PubMedCrossRefGoogle Scholar
  10. 10.
    Meltzer P, Leibovitz A, Dalton W et al (1991) Establishment of two new cell lines derived from human breast carcinomas with HER-2/neu amplification. Br J Cancer 63:727–735PubMedGoogle Scholar
  11. 11.
    Sartor CI, Dziubinski ML, Yu CL, Jove R, Ethier SP (1997) Role of epidermal growth factor receptor and STAT-3 activation in autonomous proliferation of SUM-102PT human breast cancer cells. Cancer Res 57:978–987PubMedGoogle Scholar
  12. 12.
    Bell DW, Varley JM, Szydlo TE et al (1999) Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286:2528–2531PubMedCrossRefGoogle Scholar
  13. 13.
    Lee SB, Kim SH, Bell DW et al (2001) Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res 61:8062–8067PubMedGoogle Scholar
  14. 14.
    Zheng L, Wang F, Qian C et al (2006) Unique substitution of CHEK2 and TP53 mutations implicated in primary prostate tumors and cancer cell lines. Hum Mutat 27:1062–1063PubMedCrossRefGoogle Scholar
  15. 15.
    Petitjean A, Mathe E, Kato S et al (2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Database version R12 November 2007. Hum Mutat 28:622–629PubMedCrossRefGoogle Scholar
  16. 16.
    Eshleman JR, Casey G, Kochera ME et al (1998) Chromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53. Oncogene 17:719–725PubMedCrossRefGoogle Scholar
  17. 17.
    O’Connor PM, Jackman J, Bae I et al (1997) Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res 57:4285–4300PubMedGoogle Scholar
  18. 18.
    Williams LH, Choong D, Johnson SA, Campbell IG (2006) Genetic and epigenetic analysis of CHEK2 in sporadic breast, colon, and ovarian cancers. Clin Cancer Res 12:6967–6972PubMedCrossRefGoogle Scholar
  19. 19.
    Schutte M, Seal S, Barfoot R et al (2003) Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility. Am J Hum Genet 72:1023–1028PubMedCrossRefGoogle Scholar
  20. 20.
    Cho Y, Gorina S, Jeffrey PD, Pavletich NP (1994) Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265:346–355PubMedCrossRefGoogle Scholar
  21. 21.
    Hollestelle A, Elstrodt F, Nagel JH, Kallemeijn WW, Schutte M (2007) Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines. Mol Cancer Res 5:195–201PubMedCrossRefGoogle Scholar
  22. 22.
    van de Wetering M, Barker N, Harkes IC et al (2001) Mutant E-cadherin breast cancer cells do not display constitutive Wnt signaling. Cancer Res 61:278–284PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Marijke Wasielewski
    • 1
  • Pejman Hanifi-Moghaddam
    • 1
  • Antoinette Hollestelle
    • 1
  • Sofia D. Merajver
    • 2
  • Ans van den Ouweland
    • 3
  • Jan G. M. Klijn
    • 1
  • Stephen P. Ethier
    • 4
  • Mieke Schutte
    • 1
  1. 1.Department of Medical Oncology, Josephine Nefkens InstituteErasmus University Medical CenterRotterdamThe Netherlands
  2. 2.Department of Internal MedicineUniversity of Michigan Cancer CenterAnn ArborUSA
  3. 3.Department of Clinical GeneticsErasmus University Medical CenterRotterdamThe Netherlands
  4. 4.Barbara Ann Karmanos Cancer InstituteDetroitUSA

Personalised recommendations