Genetic instability favoring transversions associated with ErbB2-induced mammary tumorigenesis

It has been argued that genetic instability is required to generate the myriad mutations that fuel tumor initiation and progression and, in fact, patients with heritable cancer susceptibility syndromes harbor defects in specific genes that normally maintain DNA integrity. However, the vast majority of human cancers arise sporadically, in the absence of deficiencies in known “mutator” genes. We used a cII-based mutation detection assay to show that the mean frequency of forward mutations in primary mammary adenocarcinomas arising in mouse mammary tumor virus-c-erbB2 transgenic mice harboring multiple copies of the λ bacteriophage genome was significantly higher than in aged-matched, wild-type mammary tissue. Analysis of the cII mutational spectrum within the mammary tumor genomic DNA demonstrated a >6-fold elevation in transversion mutation frequency, resulting in a highly unusual inversion of the transition/transversion ratio characteristic of normal epithelium; frameshift mutation frequencies were unaltered. Arising oncogenic point mutations within the c-erbB2 transgene of such tumors were predominantly transversions as well. Data from this model system support the notion that elaboration of a mutator phenotype is a consequential event in breast cancer and suggest that a novel DNA replication/repair gene is a relatively early mutational target in c-erbB2-induced mammary tumorigenesis.

[1]  N. Watanabe,et al.  The presence of single nucleotide instability in human breast cancer cell lines. , 2001, Cancer research.

[2]  L. Harris,et al.  First-Line Herceptin® Monotherapy in Metastatic Breast Cancer , 2001, Oncology.

[3]  A. Lu,et al.  Fission yeast (Schizosaccharomyces pombe) cells defective in the MutY-homologous glycosylase activity have a mutator phenotype and are sensitive to hydrogen peroxide , 2001, Zeitschrift für Induktive Abstammungs- und Vererbungslehre.

[4]  A. Jackson,et al.  The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. , 2001, Mutation research.

[5]  N. Watanabe,et al.  Single nucleotide instability without microsatellite instability in rat mammary carcinomas. , 2001, Cancer research.

[6]  Y. Yarden,et al.  Untangling the ErbB signalling network , 2001, Nature Reviews Molecular Cell Biology.

[7]  D. Slamon,et al.  Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. , 2001, Seminars in oncology.

[8]  Yosef Yarden,et al.  Molecular mechanisms underlying ErbB2/HER2 action in breast cancer , 2000, Oncogene.

[9]  J Vijg,et al.  Distinct spectra of somatic mutations accumulated with age in mouse heart and small intestine. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[10]  W. Sumanasekera,et al.  The human RAD18 gene product interacts with HHR6A and HHR6B. , 2000, Nucleic acids research.

[11]  F. Jirik,et al.  Tumors arising in DNA mismatch repair-deficient mice show a wide variation in mutation frequency as assessed by a transgenic reporter gene. , 2000, Carcinogenesis.

[12]  A. Lehmann,et al.  A novel SMC protein complex in Schizosaccharomyces pombe contains the Rad18 DNA repair protein , 2000, The EMBO journal.

[13]  D. Stern.  Tyrosine kinase signalling in breast cancer: ErbB family receptor tyrosine kinases , 2000, Breast Cancer Research.

[14]  G. R. Stuart,et al.  Mutation frequency and specificity with age in liver, bladder and brain of lacI transgenic mice. , 2000, Genetics.

[15]  Y. Hosoi,et al.  Age-associated increase of spontaneous mutant frequency and molecular nature of mutation in newborn and old lacZ-transgenic mouse. , 2000, Mutation research.

[16]  R. Liskay,et al.  Mammalian DNA mismatch repair. , 1999, Annual review of genetics.

[17]  E. Gabrielson,et al.  Microsatellite instability is uncommon in breast cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  K. Kinzler,et al.  Genetic instabilities in human cancers , 1998, Nature.

[19]  K. Tindall,et al.  Spontaneous and ENU-induced mutation spectra at the cII locus in Big Blue Rat2 embryonic fibroblasts. , 1998, Mutagenesis.

[20]  F. Jirik,et al.  Tumors of DNA mismatch repair-deficient hosts exhibit dramatic increases in genomic instability. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Ritland,et al.  Genetic modulation of neu proto-oncogene-induced mammary tumorigenesis. , 1998, Cancer research.

[22]  Jeffrey M. Hausdorff,et al.  Rapid accumulation of genome rearrangements in liver but not in brain of old mice , 1997, Nature Genetics.

[23]  A. Auerbach,et al.  Disorders of DNA replication and repair. , 1997, Current opinion in pediatrics.

[24]  A. Oppenheim,et al.  Stability of CII is a key element in the cold stress response of bacteriophage lambda infection , 1997, Journal of bacteriology.

[25]  C. Desmaze,et al.  Cloning and characterization of hOGG1, a human homolog of the OGG1 gene of Saccharomyces cerevisiae. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Yokota,et al.  Cloning of a human homolog of the yeast OGG1 gene that is involved in the repair of oxidative DNA damage , 1997, Oncogene.

[27]  J. French,et al.  Analysis of genetic instability during mammary tumor progression using a novel selection-based assay for in vivo mutations in a bacteriophage lambda transgene target. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[28]  J. Mirsalis.  Transgenic models for detection of mutations in tumors and normal tissues of rodents. , 1995, Toxicology letters.

[29]  N. Hynes,et al.  The biology of erbB-2/neu/HER-2 and its role in cancer. , 1994, Biochimica et biophysica acta.

[30]  W. Muller,et al.  Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors. , 1994, Molecular and Cellular Biology.

[31]  R. Fleischmann,et al.  Mutation of a mutL homolog in hereditary colon cancer. , 1994, Science.

[32]  D. Ward,et al.  Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer , 1994, Nature.

[33]  Robin J. Leach,et al.  Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer , 1993, Cell.

[34]  N. Copeland,et al.  The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer , 1993, Cell.

[35]  Tomas A. Prolla,et al.  Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair , 1993, Nature.

[36]  J. Short,et al.  Transgenic systems for in vivo mutation analysis. , 1993, Mutation research.

[37]  R. Cardiff,et al.  Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[38]  J. Miller,et al.  Evidence that MutY and MutM combine to prevent mutations by an oxidatively damaged form of guanine in DNA. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[39]  R. D. Gietz,et al.  Elimination of the yeast RAD6 ubiquitin conjugase enhances base-pair transitions and G.C----T.A transversions as well as transposition of the Ty element: implications for the control of spontaneous mutation. , 1992, Genetics.

[40]  F. Lottspeich,et al.  The human ubiquitin carrier protein E2(Mr = 17,000) is homologous to the yeast DNA repair gene RAD6. , 1990, The EMBO journal.

[41]  H. Land,et al.  A series of mammalian expression vectors and characterisation of their expression of a reporter gene in stably and transiently transfected cells. , 1990, Nucleic acids research.

[42]  W Godolphin,et al.  Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. , 1989, Science.

[43]  P. Leder,et al.  Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene , 1988, Cell.

[44]  J. Miller,et al.  The mutY gene: a mutator locus in Escherichia coli that generates G.C----T.A transversions. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[45]  R. Weinberg,et al.  The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen , 1984, Nature.

[46]  P. Nowell.  The clonal evolution of tumor cell populations. , 1976, Science.

[47]  L. Loeb,et al.  Errors in DNA replication as a basis of malignant changes. , 1974, Cancer research.

[48]  M. Osborn,et al.  Estrogen metabolites as bioreactive modulators of tumor initiators and promoters. , 1996, Advances in experimental medicine and biology.

[49]  B. A. Kunz,et al.  The yeast rad18 mutator specifically increases G.C----T.A transversions without reducing correction of G-A or C-T mismatches to G.C pairs. , 1991, Molecular and cellular biology.

[50]  J. Short,et al.  Analysis of spontaneous and induced mutations in transgenic mice using a lambda ZAP/lacl shuttle vector , 1991, Environmental and molecular mutagenesis.

[51]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.