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Contrasting epistatic interactions between rat quantitative trait loci controlling mammary cancer development

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Abstract

We previously defined quantitative trait loci (QTLs) that control susceptibility to 7,12-dimethylbenz(α)anthracene-induced mammary carcinoma in SPRD-Cu3 (susceptible) and WKY (resistant) rats. Two of these QTLs, assigned to chromosomes (Chr) 10 and 18, control tumor growth rate and invasiveness. In this study we characterized a congenic strain in which a large segment of WKY Chr 10 was introduced in the SPRD-Cu3 genetic background and demonstrated that this chromosome segment controls this tumor trait. The WKY allele at this QTL (Mcsta1) reduces the growth rate of the fastest growing tumors by 26%. We also previously showed that two SPRD-Cu3-WKY congenic strains containing a WKY chromosome segment derived either from Chr 5 or from Chr 18 exhibit a reduction in tumor multiplicity (QTLs Msctm1 and Mcstm2, respectively) (with no reduction in tumor growth rate in the Chr 18 congenic). In this study we generated a double congenic strain, which contains the two WKY differential segments from Chr 5 and 18, to determine how these two segments interact with one another. Interestingly, two types of epistatic interactions were found: no additive effect was seen with respect to tumor multiplicity, while a reduction in tumor growth rate was observed. It thus appears that WKY alleles located on Chr 5 and Chr 8 interact epistatically in a contrasting manner to modulate tumor multiplicity (in a nonadditive manner) and growth rate (in a synergic manner). Tumor growth rate is thus influenced by two QTLs, on Chr 10 (Mcsta1) and on Chr 18 (Mcsta2), the action of the latter being dependent on the presence of the Chr5 QTL (Mcstm1). The expression level of positional and functional candidate genes was also analyzed. On Chr 5, Pla2g2a is subject to a syntenic control while expression of the Tp53 (Chr 10) and Pmai1/Noxa (Chr 18) genes appears to be controlled by several mammary cancer resistance QTLs.

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References

  • 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

    CAS  PubMed  Google Scholar 

  • Blakely CM, Stoddard AJ, Belka GK, Dugan KD, Notarfrancesco KL et al (2006) Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy. Cancer Res 66:6421–6431

    Article  CAS  PubMed  Google Scholar 

  • Bradbury AR, Olopade OI (2007) Genetic susceptibility to breast cancer. Rev Endocr Metab Disord 8:255–267

    Article  PubMed  Google Scholar 

  • Brody JG, Rudel RA, Michels KB, Moysich KB, Bernstein L et al (2007) Environmental pollutants, diet, physical activity, body size, and breast cancer: where do we stand in research to identify opportunities for prevention? Cancer 109:2627–2634

    Article  PubMed  Google Scholar 

  • Carlborg O, Haley CS (2004) Epistasis: too often neglected in complex trait studies? Nat Rev Genet 5:618–625

    Article  CAS  PubMed  Google Scholar 

  • Collaborative Group on Hormonal Factors in Breast Cancer (2001) Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiologic studies including 58, 209 women with breast cancer and 101, 986 women without the disease. Lancet 358:1389–1399

    Article  Google Scholar 

  • Cormier RT, Hong KH, Halberg RB, Hawkins TL, Richardson P et al (1997) Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis. Nat Genet 17:88–91

    Article  CAS  PubMed  Google Scholar 

  • Di Leonardo A, Linke SP, Clarkin K, Wahl GM (1994) DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev 8:2540–2551

    Article  CAS  PubMed  Google Scholar 

  • Gould MN (1995) Rodent models for the study of etiology, prevention and treatment of breast cancer. Semin Cancer Biol 6:147–152

    Article  CAS  PubMed  Google Scholar 

  • Jiang J, Neubauer BL, Graff JR, Chedid M, Thomas JE et al (2002) Expression of group IIA secretory phospholipase A2 is elevated in prostatic intraepithelial neoplasia and adenocarcinoma. Am J Pathol 160:667–671

    CAS  PubMed  Google Scholar 

  • Lan H, Kendziorski CM, Haag JD, Shepel LA, Newton MA et al (2001) Genetic loci controlling breast cancer susceptibility in the Wistar-Kyoto rat. Genetics 157:331–339

    CAS  PubMed  Google Scholar 

  • Le Voyer T, Lu Z, Babb J, Lifsted T, Williams M et al (2000) An epistatic interaction controls the latency of a transgene-induced mammary tumor. Mamm Genome 11:883–889

    Article  CAS  PubMed  Google Scholar 

  • Lella V, Stieber D, Riviere M, Szpirer J, Szpirer C (2007) Mammary cancer resistance and precocious mammary differentiation in the WKY rat: identification of 2 quantitative trait loci. Int J Cancer 121:1738–1743

    Article  CAS  PubMed  Google Scholar 

  • Monti J, Plehm R, Schulz H, Ganten D, Kreutz R et al (2003) Interaction between blood pressure quantitative trait loci in rats in which trait variation at chromosome 1 is conditional upon a specific allele at chromosome 10. Hum Mol Genet 12:435–439

    Article  CAS  PubMed  Google Scholar 

  • Moore JH (2003) The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum Hered 56:73–82

    Article  PubMed  Google Scholar 

  • Moore CJ, Tricomi WA, Gould MN (1988) Comparison of 7, 12-dimethylbenz[a]anthracene metabolism and DNA binding in mammary epithelial cells from three rat strains with differing susceptibilities to mammary carcinogenesis. Carcinogenesis 9:2099–2102

    Article  CAS  PubMed  Google Scholar 

  • Moreno C, Kaldunski ML, Wang T, Roman RJ, Greene AS et al (2007) Multiple blood pressure loci on rat chromosome 13 attenuate development of hypertension in the Dahl S hypertensive rat. Physiol Genomics 31:228–235

    Article  CAS  PubMed  Google Scholar 

  • Norbury CJ, Zhivotovsky B (2004) DNA damage-induced apoptosis. Oncogene 23:2797–2808

    Article  CAS  PubMed  Google Scholar 

  • Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T et al (2000) Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288:1053–1058

    Article  CAS  PubMed  Google Scholar 

  • Parkin DM (2004) International variation. Oncogene 23:6329–6340

    Article  CAS  PubMed  Google Scholar 

  • Peto J, Mack TM (2000) High constant incidence in twins and other relatives of women with breast cancer. Nat Genet 26:411–414

    Article  CAS  PubMed  Google Scholar 

  • Quan X, Laes JF, Stieber D, Riviere M, Russo J et al (2006) Genetic identification of distinct loci controlling mammary tumor multiplicity, latency, and aggressiveness in the rat. Mamm Genome 17:310–321

    Article  CAS  PubMed  Google Scholar 

  • Rapp JP, Garrett MR, Deng AY (1998) Construction of a double congenic strain to prove an epistatic interaction on blood pressure between rat chromosomes 2 and 10. J Clin Invest 101:1591–1595

    Article  CAS  PubMed  Google Scholar 

  • Rudel RA, Attfield KR, Schifano JN, Brody JG (2007) Chemicals causing mammary gland tumors in animals signal new directions for epidemiology, chemicals testing, and risk assessment for breast cancer prevention. Cancer 109:2635–2666

    Article  CAS  PubMed  Google Scholar 

  • Russo J, Gusterson BA, Rogers AE, Russo IH, Wellings SR et al (1990) Comparative study of human and rat mammary tumorigenesis. Lab Invest 62:244–278

    CAS  PubMed  Google Scholar 

  • Samuelson DJ, Hesselson SE, Aperavich BA, Zan Y, Haag JD et al (2007) Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk. Proc Natl Acad Sci U S A 104:6299–6304

    Article  CAS  PubMed  Google Scholar 

  • Schaffer BS, Lachel CM, Pennington KL, Murrin CR, Strecker TE et al (2006) Genetic bases of estrogen-induced tumorigenesis in the rat: mapping of loci controlling susceptibility to mammary cancer in a Brown Norway × ACI intercross. Cancer Res 66:7793–7800

    Article  CAS  PubMed  Google Scholar 

  • Shepel LA, Gould MN (1999) The genetic components of susceptibility to breast cancer in the rat. Prog Exp Tumor Res 35:158–169

    Article  CAS  PubMed  Google Scholar 

  • Shull JD (2007) The rat oncogenome: comparative genetics and genomics of rat models of mammary carcinogenesis. Breast Dis 28:69–86

    CAS  PubMed  Google Scholar 

  • Stieber D, Piessevaux G, Riviere M, Laes JF, Quan X et al (2007) Isolation of two regions on rat chromosomes 5 and 18 affecting mammary cancer susceptibility. Int J Cancer 120:1678–1683

    Article  CAS  PubMed  Google Scholar 

  • Stratton MR, Rahman N (2008) The emerging landscape of breast cancer susceptibility. Nat Genet 40:17–22

    Article  CAS  PubMed  Google Scholar 

  • Szpirer C, Szpirer J (2007) Mammary cancer susceptibility: human genes and rodent models. Mamm Genome 18:817–831

    Article  PubMed  Google Scholar 

  • Welsch CW (1985) Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: a review and tribute to Charles Brenton Huggins. Cancer Res 45:3415–3443

    CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Pascale Van Vooren for technical assistance. This work was supported by the National Fund for Scientific Medical Research (FRSM), the National Fund for Scientific Research (FNRS, Télévie), and the FP6 program EURATools. G. Piessevaux was supported by a FRIA fellowship. C. Szpirer is a Research Director at the FNRS (Belgium).

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Authors and Affiliations

  1. Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Rue Profs Jeener & Brachet, 12, 6041, Gosselies (Charleroi), Belgium

    Géraldine Piessevaux, Virginie Lella, Michèle Rivière, Daniel Stieber, Pierre Drèze, Josiane Szpirer & Claude Szpirer

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  1. Géraldine Piessevaux
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  2. Virginie Lella
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  3. Michèle Rivière
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  4. Daniel Stieber
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  5. Pierre Drèze
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  6. Josiane Szpirer
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  7. Claude Szpirer
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Correspondence to Claude Szpirer.

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Piessevaux, G., Lella, V., Rivière, M. et al. Contrasting epistatic interactions between rat quantitative trait loci controlling mammary cancer development. Mamm Genome 20, 43–52 (2009). https://doi.org/10.1007/s00335-008-9155-4

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  • DOI: https://doi.org/10.1007/s00335-008-9155-4

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