Skip to main content

Advertisement

SpringerLink
Log in

Mammary tumor modifiers in BALB/cJ mice heterozygous for p53

  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

BALB/c mice are predisposed to developing spontaneous mammary tumors, which are further increased in a p53 heterozygous state. C57BL/6J mice are resistant to induced mammary tumors and develop less than 1% mammary tumors in both wild-type and p53 +/− states. To map modifiers of mammary tumorigenesis, we have established F1 and F2 crosses and backcrosses to BALB/cJ (N2-BALB/cJ) and C57BL/6J (N2-C57BL/6J) strains. All cohorts developed mammary carcinomas in p53 +/− females, suggesting that multiple loci dominantly and recessively contributed to mammary tumorigenesis. We mapped two modifiers of mammary tumorigenesis in the BALB/cJ strain. Mtsm1 (mammary tumor susceptibility modifier), a dominant-acting modifier, is located on chromosome 7. Mtsm1 is suggestive for linkage to mammary tumorigenesis (p = 0.001). We have analyzed the Mtsm1 region to locate candidate genes by comparing it to a rat modifier region, Mcs3, which shares syntenic conservation with Mtsm1. Expression data and SNPs were also taken into account. Five potential candidate genes within Mtsm1 are Aldh1a3, Chd2, Nipa2, Pcsk6, and Tubgcp5. The second modifier mapped is Mtsm2, a recessive-acting modifier. Mtsm2 is located on chromosome X and is significantly linked to mammary tumorigenesis (p = 1.03 × 10−7).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Altman PL, Katz DD (1979) Inbred and genetically defined strains of laboratory animals (Bethesda, MD: Federation of American Societies for Experimental Biology)

  • Balmain A, Gray J, Ponder B (2003) The genetics and genomics of cancer. Nat Genet 33 Suppl:238–244

    Article  PubMed  CAS  Google Scholar 

  • Blackburn AC, Brown JS, Naber SP, Otis CN, Wood JT, et al. (2003) BALB/c alleles for Prkdc and Cdkn2a interact to modify tumor susceptibility in Trp53+/− mice. Cancer Res 63:2364–2368

    PubMed  CAS  Google Scholar 

  • Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, et al. (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119:591–602

    Article  PubMed  CAS  Google Scholar 

  • Bond GL, Hu W, Levine A (2005) A single nucleotide polymorphism in the MDM2 gene: from a molecular and cellular explanation to clinical effect. Cancer Res 65:5481–5484

    Article  PubMed  CAS  Google Scholar 

  • Brown BW, Costello TJ, Hwang SJ, Strong LC (2005) Generation or birth cohort effect on cancer risk in Li-Fraumeni syndrome. Hum Genet 118:489–498

    Article  PubMed  Google Scholar 

  • Chai JH, Locke DP, Greally JM, Knoll JH, Ohta T, et al. (2003) Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons. Am J Hum Genet 73:898–925

    Article  PubMed  CAS  Google Scholar 

  • Cheng M, Watson PH, Paterson JA, Seidah N, Chretien M, et al. (1997) Pro-protein convertase gene expression in human breast cancer. Int J Cancer 71:966–971

    Article  PubMed  CAS  Google Scholar 

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA Jr, et al. (1992) Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356:215–221

    Article  PubMed  CAS  Google Scholar 

  • Donehower LA, Harvey M, Vogel H, McArthur MJ, Montgomery CA Jr, et al. (1995) Effects of genetic background on tumorigenesis in p53-deficient mice. Mol Carcinog 14:16–22

    Article  PubMed  CAS  Google Scholar 

  • Eppig JT, Bult CJ, Kadin JA, Richardson JE, Blake JA, et al. (2005) The Mouse Genome Database (MGD): from genes to mice—a community resource for mouse biology. Nucleic Acids Res 33:D471–D475

    Article  PubMed  CAS  Google Scholar 

  • Evans SC, Lozano G (1997) The Li-Fraumeni syndrome: an inherited susceptibility to cancer. Mol Med Today 3:390–395

    Article  PubMed  CAS  Google Scholar 

  • Harvey M, McArthur MJ, Montgomery CA Jr, Bradley A, Donehower LA (1993) Genetic background alters the spectrum of tumors that develop in p53-deficient mice. FASEB J 7:938–943

    PubMed  CAS  Google Scholar 

  • Heston WE, Vlahakis G (1971) Mammary tumors, plaques, and hyperplastic alveolar nodules in various combinations of mouse inbred strains and the different lines of the mammary tumor virus. Int J Cancer 7:141–148

    Article  PubMed  CAS  Google Scholar 

  • Hwang SJ, Cheng LS, Lozano G, Amos CI, Gu X, et al. (2003) Lung cancer risk in germline p53 mutation carriers: association between an inherited cancer predisposition, cigarette smoking, and cancer risk. Hum Genet 113:238–243

    Article  PubMed  CAS  Google Scholar 

  • Iwakuma T, Parant JM, Fasulo M, Zwart E, Jacks T, et al. (2004) Mutation at p53 serine 389 does not rescue the embryonic lethality in mdm2 or mdm4 null mice. Oncogene 23:7644–7650

    Article  PubMed  CAS  Google Scholar 

  • Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, et al. (1994) Tumor spectrum analysis in p53-mutant mice. Curr Biol 4:1–7

    Article  PubMed  CAS  Google Scholar 

  • Kleihues P, Schauble B, zur Hausen A, Esteve J, Ohgaki H (1997) Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol 150:1–13

    PubMed  CAS  Google Scholar 

  • Kuperwasser C, Hurlbut GD, Kittrell FS, Dickinson ES, Laucirica R, et al. (2000) Development of spontaneous mammary tumors in BALB/c p53 heterozygous mice. A model for Li-Fraumeni syndrome Am J Pathol 157:2151–2159

    PubMed  CAS  Google Scholar 

  • Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247

    Article  PubMed  CAS  Google Scholar 

  • Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, et al. (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250:1233–1238

    Article  PubMed  CAS  Google Scholar 

  • Mira YLR, Zheng WL, Kuppumbatti YS, Rexer B, Jing Y, et al. (2000) Retinol conversion to retinoic acid is impaired in breast cancer cell lines relative to normal cells. J Cell Physiol 185:302–309

    Article  Google Scholar 

  • Murphy SM, Preble AM, Patel UK, O’Connell KL, Dias DP, et al. (2001) GCP5 and GCP6: two new members of the human gamma-tubulin complex. Mol Biol Cell 12:3340–3352

    PubMed  CAS  Google Scholar 

  • Rebbeck TR, Kantoff PW, Krithivas K, Neuhausen S, Blackwood MA, et al. (1999) Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet 64:1371–1377

    Article  PubMed  CAS  Google Scholar 

  • Rexer BN, Zheng WL, Ong DE (2001) Retinoic acid biosynthesis by normal human breast epithelium is via aldehyde dehydrogenase 6, absent in MCF-7 cells. Cancer Res 61:7065–7070

    PubMed  CAS  Google Scholar 

  • Shepel LA, Lan H, Haag JD, Brasic GM, Gheen ME, et al. (1998) Genetic identification of multiple loci that control breast cancer susceptibility in the rat. Genetics 149:289–299

    PubMed  CAS  Google Scholar 

  • Srivastava S, Zou ZQ, Pirollo K, Blattner W, Chang EH (1990) Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 348:747–749

    Article  PubMed  CAS  Google Scholar 

  • Trkova M, Hladikova M, Kasal P, Goetz P, Sedlacek Z (2002) Is there anticipation in the age at onset of cancer in families with Li-Fraumeni syndrome? J Hum Genet 47:381–386

    Article  PubMed  Google Scholar 

  • Vitezica ZG, Elsen JM, Rupp R, Diaz C (2005) Using genotype probabilities in survival analysis: a scrapie case. Genet Sel Evol 37:403–415

    Article  PubMed  Google Scholar 

  • Wingo PA, Ries LA, Rosenberg HM, Miller DS, Edwards BK (1998) Cancer incidence and mortality, 1973–1995: a report card for the U.S. Cancer 82:1197–1207

    Article  PubMed  CAS  Google Scholar 

  • Woodage T, Basrai MA, Baxevanis AD, Hieter P, Collins FS (1997) Characterization of the CHD family of proteins. Proc Natl Acad Sci U S A 94:11472–11477

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

These studies were supported by fellowships from the American Legion Auxiliary and Schissler Family Foundation to JGK, the training grants in Molecular Genetics of Cancer (CA009299) UO1 CA-04-002 and PO1 CA34936 to GL, and the Cancer Center Support Grant (CA16672) to M. D. Anderson Cancer Center.

Author information

Author notes

  1. Anneke C. Blackburn

    Present address: John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia

Authors and Affiliations

  1. The University of Texas Graduate School of Biomedical Sciences and the Department of Cancer Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, USA

    Joanna G. Koch, Melissa V. Olson & Guillermina Lozano

  2. Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, USA

    Xiangjun Gu, Younghun Han & Christopher I. Amos

  3. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, 77030, USA

    Adel K. El-Naggar

  4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, 77030, USA

    Daniel Medina

  5. Department of Veterinary and Animal Sciences, Molecular and Cellular Biology Program, University of Massachusetts, Amherst, Massachusetts, 01003, USA

    D. Joseph Jerry & Anneke C. Blackburn

  6. Pioneer Valley Life Sciences Institute, Springfield, Massachusetts, 01199, USA

    D. Joseph Jerry

  7. Roche Palo Alto, Palo Alto, California, 94304, USA

    Gary Peltz

  8. Department of Cancer Genetics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe, Box 1010, Houston, TX , 77030, USA

    Guillermina Lozano

Authors
  1. Joanna G. Koch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiangjun Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Younghun Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adel K. El-Naggar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Melissa V. Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniel Medina
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D. Joseph Jerry
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anneke C. Blackburn
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gary Peltz
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christopher I. Amos
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Guillermina Lozano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guillermina Lozano.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Koch, J.G., Gu, X., Han, Y. et al. Mammary tumor modifiers in BALB/cJ mice heterozygous for p53 . Mamm Genome 18, 300–309 (2007). https://doi.org/10.1007/s00335-007-9028-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00335-007-9028-2

Keywords

Search

Navigation