Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bartek J, Lukas J (2003) Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell 3:421–429
Ahn J, Urist M, Prives C (2004) The Chk2 protein kinase. DNA Repair (Amst) 3:1039–1047
Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439
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 31:55–59
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 71:432–438
Nevanlinna H, Bartek J (2006) The CHEK2 gene and inherited breast cancer susceptibility. Oncogene 25:5912–5919
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 99:97–101
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 81:103–108
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 66:41–45
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 63:727–735
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 57:978–987
Bell DW, Varley JM, Szydlo TE et al (1999) Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286:2528–2531
Lee SB, Kim SH, Bell DW et al (2001) Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. Cancer Res 61:8062–8067
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 27:1062–1063
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 28:622–629
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 17:719–725
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 57:4285–4300
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 12:6967–6972
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 72:1023–1028
Cho Y, Gorina S, Jeffrey PD, Pavletich NP (1994) Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265:346–355
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 5:195–201
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 61:278–284
Acknowledgement
Funding was provided by the Dutch Cancer Society, grant DDHK 2003-2862
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wasielewski, M., Hanifi-Moghaddam, P., Hollestelle, A. et al. Deleterious CHEK2 1100delC and L303X mutants identified among 38 human breast cancer cell lines. Breast Cancer Res Treat 113, 285–291 (2009). https://doi.org/10.1007/s10549-008-9942-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-008-9942-3