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Induced mammary cancer in rat models: pathogenesis, genetics, and relevance to female breast cancer

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Abstract

Mammary cancer, or breast cancer in women, is a polygenic disease with a complex etiopathogenesis. While much remains elusive regarding its origin, it is well established that chemical carcinogens and endogenous estrogens contribute significantly to the initiation and progression of this disease. Rats have been useful models to study induced mammary cancer. They develop mammary tumors with comparable histopathology to humans and exhibit differences in resistance or susceptibility to mammary cancer depending on strain. While some rat strains (e.g., Sprague-Dawley) readily form mammary tumors following treatment with the chemical carcinogen, 7,12-dimethylbenz[a]-anthracene (DMBA), other strains (e.g., Copenhagen) are resistant to DMBA-induced mammary carcinogenesis. Genetic linkage in inbred strains has identified strain-specific quantitative trait loci (QTLs) affecting mammary tumors, via mechanisms that act together to promote or attenuate, and include 24 QTLs controlling the outcome of chemical induction, 10 QTLs controlling the outcome of estrogen induction, and 4 QTLs controlling the outcome of irradiation induction. Moreover, and based on shared factors affecting mammary cancer etiopathogenesis between rats and humans, including orthologous risk regions between both species, rats have served as useful models for identifying methods for breast cancer prediction and treatment. These studies in rats, combined with alternative animal models that more closely mimic advanced stages of breast cancer and/or human lifestyles, will further improve our understanding of this complex disease.

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References

  1. DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Goding Sauer A, et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69:438–51. https://doi.org/10.3322/caac.21583.

    Article  PubMed  Google Scholar 

  2. Rudolph A, Chang-Claude J, Schmidt MK. Gene-environment interaction and risk of breast cancer. Br J Cancer. 2016;114:125–33. https://doi.org/10.1038/bjc.2015.439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bernstein L. Epidemiology of endocrine-related risk factors for breast cancer. J Mammary Gland Biol Neoplasia. 2002;7:3–15. https://doi.org/10.1023/A:1015714305420.

    Article  PubMed  Google Scholar 

  4. Tamimi RM, Spiegelman D, Smith-Warner SA, Wang M, Pazaris M, Willett WC, et al. Population Attributable Risk of Modifiable and Nonmodifiable Breast Cancer Risk Factors in Postmenopausal Breast Cancer. Am J Epidemiol. 2016;184:884–93. https://doi.org/10.1093/aje/kww145.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Byrne C, Ursin G, Martin CF, Peck JD, Cole EB, Zeng D, et al. Mammographic Density Change With Estrogen and Progestin Therapy and Breast Cancer Risk. J Natl Cancer Inst. 2017;109:djx001. https://doi.org/10.1093/jnci/djx001.

    Article  CAS  PubMed Central  Google Scholar 

  6. McDonald JA, Goyal A, Terry MB. Alcohol Intake and Breast Cancer Risk: Weighing the Overall Evidence. Curr Breast Cancer Rep. 2013;5:208–21. https://doi.org/10.1007/s12609-013-0114-z.

    Article  Google Scholar 

  7. Odefrey F, Stone J, Gurrin LC, Byrnes GB, Apicella C, Dite GS, et al. Common genetic variants associated with breast cancer and mammographic density measures that predict disease. Cancer Res. 2010;70:1449–58. https://doi.org/10.1158/0008-5472.CAN-09-3495.

    Article  CAS  PubMed  Google Scholar 

  8. Mahdavi M, Nassiri M, Kooshyar MM, Vakili-Azghandi M, Avan A, Sandry R, et al. Hereditary breast cancer; Genetic penetrance and current status with BRCA. J Cell Physiol. 2018;234:5741–50. https://doi.org/10.1002/jcp.27464.

    Article  CAS  PubMed  Google Scholar 

  9. Mceuen CS. Occurrence of cancer in rats treated with oestrone. Am J Cancer. 1938;34:184–95.

    CAS  PubMed  Google Scholar 

  10. Isaacs JT. Genetic Control of Resistance to Chemically Induced Mammary Adenocarcinogenesis in the Rat. Cancer Res. 1986;46:3958–63.

    CAS  PubMed  Google Scholar 

  11. Russo J, Russo IH. Experimentally induced mammary tumors in rats. Breast Cancer Res Treat. 1996;39:7–20. https://doi.org/10.1007/BF01806074.

    Article  CAS  PubMed  Google Scholar 

  12. Jerry DJ, Shull JD, Hadsell DL, Rijnkels M, Dunphy KA, Schneider SS, et al. Genetic variation in sensitivity to estrogens and breast cancer risk. Mamm Genome. 2018;29:24–37. https://doi.org/10.1007/s00335-018-9741-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Russo IH, Russo J. Role of Hormones in Mammary Cancer Initiation and Progression. J Mammary Gland Biol Neoplasia. 1998;3:49–61. https://doi.org/10.1023/A:1018770218022.

    Article  CAS  PubMed  Google Scholar 

  14. Alvarado A, Faustino-Rocha AI, Colaço B, Oliveira PA. Experimental mammary carcinogenesis - Rat models. Life Sci. 2017;173:116–34. https://doi.org/10.1016/j.lfs.2017.02.004.

    Article  CAS  PubMed  Google Scholar 

  15. Smits B, van Zutphen B, Plasterk R, Cuppen E. Genetic variation in coding regions between and within commonly used inbred rats strains. Genome Res. 2004;14:1285–90. https://doi.org/10.1101/gr.2155004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Szpirer C, Szpirer J. Mammary cancer susceptibility: human genes and rodent models. Mamm Genome. 2007;18:817–31. https://doi.org/10.1007/s00335-007-9073-x.

    Article  PubMed  Google Scholar 

  17. Luzhna L, Kutanzi K, Kovalchuk O. Gene expression and epigenetic profiles of mammary gland tissue: Insight into the differential predisposition of four rat strains to mammary gland cancer. Mutat Res Genet Toxicol Environ Mutagen. 2015;779:39–56. https://doi.org/10.1016/j.mrgentox.2014.07.006.

    Article  CAS  PubMed  Google Scholar 

  18. Shull JD. The rat oncogenome: Comparative genetics and genomics of rat models of mammary carcinogenesis. Breast Dis. 2007;28:69–86. https://doi.org/10.3233/BD-2007-28108.

    Article  CAS  PubMed  Google Scholar 

  19. Wood GA, Korkola JE, Archer MC. Tissue-specific resistance to cancer development in the rat: phenotypes of tumor-modifier genes. Carcinogenesis. 2002;23:1–9. https://doi.org/10.1093/carcin/23.1.1.

    Article  PubMed  Google Scholar 

  20. Russo J, Russo IH. Atlas and histologic classification of tumors of the rat mammary gland. J Mammary Gland Biol Neoplasia. 2000;5:187–200. https://doi.org/10.1023/A:1026443305758.

    Article  CAS  PubMed  Google Scholar 

  21. Russo IH, Russo J. Mammary Gland Neoplasia in Long-Term Rodent Studies. Environ Health Perspect. 1996;104:938–67. https://doi.org/10.1289/ehp.96104938.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Samuelson E, Nilsson J, Walentinsson A, Szpirer C, Behboudi A. Absence of Ras mutations in rat DMBA-induced mammary tumors. Mol Carcinog. 2009;48:150–5. https://doi.org/10.1002/mc.20464.

    Article  CAS  PubMed  Google Scholar 

  23. Adamovic T, McAllister D, Rowe JJ, Wang T, Jacob HJ, Sugg SL. Genetic mapping of mammary tumor traits to rat chromosome 10 using a novel panel of consomic rats. Cancer Genet Cytogenet. 2008;186:41–8. https://doi.org/10.1016/j.cancergencyto.2008.05.014.

    Article  CAS  PubMed  Google Scholar 

  24. Schedin P, Mitrenga T, McDaniel S, Kaeck M. Mammary ECM Composition and function are altered by reproductive state. Mol Carcinog. 2004;41:207–20. https://doi.org/10.1002/mc.20058.

    Article  CAS  PubMed  Google Scholar 

  25. Masso-Welch PA, Darcy KM, Stangle-Castor NC, Ip MM. A Developmental Atlas of Rat Mammary Gland Histology. J Mammary Gland Biol Neoplasia. 2000;5:165–85. https://doi.org/10.1023/A:1026491221687.

    Article  CAS  PubMed  Google Scholar 

  26. Eighmy JJ, Sharma AK, Blackshear PE. Chapter 21 - Mammary Gland. In: Suttie AW, editor. Boorman’s Pathol Rat. Second. Academic Press; 2018. pp. 369–87.

  27. Fu NY, Nolan E, Lindeman GJ, Visvader JE. Stem cells and the differentiation hierarchy in mammary gland development. Physiol Rev. 2020;100:489–523. https://doi.org/10.1152/physrev.00040.2018.

    Article  CAS  PubMed  Google Scholar 

  28. van Zwieten MJ. Normal Anatomy and Pathology of the Rat Mammary Gland. Rat as Anim Model Breast Cancer Res A Histopathol study radiation- Horm rat mammary tumors. Dordrecht: Springer Netherlands; 1984. pp. 53–134.

    Google Scholar 

  29. Avagliano A, Fiume G, Ruocco MR, Martucci N, Vecchio E, Insabato L, et al. Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination. Cancers (Basel). 2020;12:1697. https://doi.org/10.3390/cancers12061697.

    Article  CAS  Google Scholar 

  30. Unsworth A, Anderson R, Britt K. Stromal fibroblasts and the immune microenvironment: Partners in mammary gland biology and pathology? J Mammary Gland Biol Neoplasia. 2014;19:169–82. https://doi.org/10.1007/s10911-014-9326-8.

    Article  PubMed  Google Scholar 

  31. Paine IS, Lewis MT. The Terminal End Bud: the Little Engine that Could. J Mammary Gland Biol Neoplasia. 2017;22:93–108. https://doi.org/10.1007/s10911-017-9372-0.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Slepicka PF, Somasundara AVH, dos Santos CO. The molecular basis of mammary gland development and epithelial differentiation. Semin Cell Dev Biol. 2021;114:93–112. https://doi.org/10.1016/j.semcdb.2020.09.014.

    Article  PubMed  Google Scholar 

  33. Rios AC, Fu NY, Lindeman GJ, Visvader JE. In situ identification of bipotent stem cells in the mammary gland. Nature. 2014;506:322–6. https://doi.org/10.1038/nature12948.

    Article  CAS  PubMed  Google Scholar 

  34. Pandey PR, Saidou J, Watabe K. Role of myoepithelial cells in breast tumor progression. Front Biosci. 2010;15:226–36. https://doi.org/10.2741/3617.

    Article  CAS  PubMed Central  Google Scholar 

  35. Yurchenco PD, Patton BL. Developmental and Pathogenic Mechanisms of Basement Membrane Assembly. Curr Pharm Des. 2009;15:1277–94. https://doi.org/10.2174/138161209787846766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Macias H, Hinck L. Mammary gland development. WIREs Dev Biol. 2012;1:533–57. https://doi.org/10.1002/wdev.35.

    Article  CAS  Google Scholar 

  37. Cristea S, Polyak K. Dissecting the mammary gland one cell at a time. Nat Commun. 2018;9:2473. https://doi.org/10.1038/s41467-018-04905-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Iannaccone PM, Jacob HJ. Rats! Dis Model Mech. 2009;2:206–10. https://doi.org/10.1242/dmm.002733.

    Article  PubMed  Google Scholar 

  39. Russo J. Significance of Rat mammary tumors for human risk assessment. Toxicol Pathol. 2015;43:145–70. https://doi.org/10.1177%2F0192623314532036.

    Article  CAS  PubMed  Google Scholar 

  40. Szpirer C. Rat models of human diseases and related phenotypes: A systematic inventory of the causative genes. J Biomed Sci. 2020;27:84. https://doi.org/10.1186/s12929-020-00673-8.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Greenacre CB. Spontaneous tumors of small mammals. Vet Clin North Am Exot Anim Pract. 2004;7:627–51. https://doi.org/10.1016/j.cvex.2004.04.009.

    Article  PubMed  Google Scholar 

  42. Nakazawa M, Tawaratani T, Uchimoto H, Kawaminami A, Ueda M, Ueda A, et al. Spontaneous neoplastic lesions in aged Sprague-Dawley rats. Exp Anim. 2001;50:99–103. https://doi.org/10.1538/expanim.50.99.

    Article  CAS  PubMed  Google Scholar 

  43. Asamoto M, Toriyama-Baba H, Ohnishi T, Naito A, Ota T, Ando A, et al. Transgenic rats carrying human c-Ha-ras proto-oncogene are highly susceptible to N-nitrosomethylbenzylamine induction of esophageal tumorigenesis. Japanese J cancer Res. 2005;93:744–51. https://doi.org/10.1111/j.1349-7006.2002.tb01315.x.

    Article  Google Scholar 

  44. Nohmi T, Masumura K, Toyoda-Hokaiwado N. Transgenic rat models for mutagenesis and carcinogenesis. Genes Environ. 2017;39:11. https://doi.org/10.1186/s41021-016-0072-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Flister MJ, Joshi A, Bergom C, Rui H. Mapping Mammary Tumor Traits in the Rat. In: Hayman G, Smith J, Dwinell M, Shimoyama M, editors. Rat Genomics Methods Mol Biol. New York: Humana; 2019. pp. 249–67.

    Chapter  Google Scholar 

  46. Russo J, Tay LK, Russo IH. Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res Treat. 1982;2:5–73. https://doi.org/10.1007/BF01805718.

    Article  CAS  PubMed  Google Scholar 

  47. Alvarado A, Lopes AC, Faustino-Rocha AI, Cabrita AMS, Ferreira R, Oliveira PA, et al. Prognostic factors in MNU and DMBA-induced mammary tumors in female rats. Pathol Res Pract. 2017;213:441–6. https://doi.org/10.1016/j.prp.2017.02.014.

    Article  CAS  PubMed  Google Scholar 

  48. Ariazi JL, Haag JD, Lindstrom MJ, Gould MN. Mammary glands of sexually immature rats are more susceptible than those of mature rats to the carcinogenic, lethal, and mutagenic effects of N-nitroso-N-methylurea. Mol Carcinog. 2005;43:155–64. https://doi.org/10.1002/mc.20104.

    Article  CAS  PubMed  Google Scholar 

  49. Grubbs CJ, Peckham JC, Cato KD. Mammary carcinogenesis in rats in relation to age at time of N-nitroso-N-methylurea administration. J Natl Cancer Inst. 1983;70:209–12.

    CAS  PubMed  Google Scholar 

  50. Korsh J, Shen A, Aliano K, Davenport T. Polycyclic Aromatic Hydrocarbons and Breast Cancer: A Review of the Literature. Breast Care. 2015;10:316–8. https://doi.org/10.1159/000436956.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Guengerich FP. Roles of cytochrome P-450 enzymes in chemical carcinogenesis and cancer chemotherapy. Cancer Res. 1988;48:2946–54.

    CAS  PubMed  Google Scholar 

  52. Lin Y, Yao Y, Liu S, Wang L, Moorthy B, Xiong D, et al. Role of mammary epithelial and stromal P450 enzymes in the clearance and metabolic activation of 7,12-dimethylbenz(a)anthracene in mice. Toxicol Lett. 2012;212:97–105. https://doi.org/10.1016/j.toxlet.2012.05.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kerdelhué B, Forest C, Coumoul X. Dimethyl-Benz(a)anthracene: A mammary carcinogen and a neuroendocrine disruptor. Biochim Open. 2016;3:49–55. https://doi.org/10.1016/j.biopen.2016.09.003.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Daniel FB, Joyce NJ. 7,12-dimethylbenz[a]anthracene-DNA adducts in sprague-dawley and long-evans female rats: The relationship of DNA adducts to mammary cancer. Carcinogenesis. 1984;5:1021–6. https://doi.org/10.1093/carcin/5.8.1021.

    Article  CAS  PubMed  Google Scholar 

  55. Faustino-Rocha AI, Ferreira R, Oliveira PA, Gama A, Ginja M. N-Methyl-N-nitrosourea as a mammary carcinogenic agent. Tumor Biol. 2015;36:9095–117. https://doi.org/10.1007/s13277-015-3973-2.

    Article  CAS  Google Scholar 

  56. Sukumar S, Notario V, Martin-Zanca D, Barbacid M. Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-1 locus by single point mutations. Nature. 1983;306:658–61. https://doi.org/10.1038/306658a0.

    Article  CAS  PubMed  Google Scholar 

  57. Dao TL. The Role of Ovarian Hormones in Initiating the Induction of Mammary Cancer in Rats by Polynuclear Hydrocarbons. Cancer Res. 1962;22:973–81.

    CAS  PubMed  Google Scholar 

  58. Wilkinson JR, Williams JC, Singh D, Goss PE, Easton D, Coombes RC. Response of Nitrosomethylurea-induced Rat Mammary Tumor to Endocrine Therapy and Comparison with Clinical Response. Cancer Res. 1986;46:4862–5.

    CAS  PubMed  Google Scholar 

  59. Braun RJ, Pezzuto JM, Anderson CH, Beattie CW. Estrous cycle status alters N-methyl-N-nitrosourea (NMU)-induced rat mammary tumor growth and regression. Cancer Lett. 1989;48:205–11. https://doi.org/10.1016/0304-3835(89)90119-5.

    Article  CAS  PubMed  Google Scholar 

  60. Russo IH, Tewari M, Russo J. Morphology and Development of the Rat Mammary Gland. In: Jones TC, Mohr U, Hunt RD, editors. Integument Mammary Gland Monogr Pathol Lab Anim (Sponsored by Int Life Sci Institute). Berlin: Springer; 1989. pp. 233–52.

    Chapter  Google Scholar 

  61. Tay L, Russo J. Formation and removal of 7,12-dimethylbenz[a]anthracene–nucleic acid adducts in rat mammary epithelial cells with different susceptibility to carcinogenesis. Carcinogenesis. 1981;2:1327–33. https://doi.org/10.1093/carcin/2.12.1327.

    Article  CAS  PubMed  Google Scholar 

  62. Russo J, Saby J, Isenberg WM, Russo IH. Pathogenesis of Mammary Carcinomas Induced in Rats by 7, 12-Dimethylbenz[a]anthracene. J Natl Cancer Inst. 1977;59:435–45. https://doi.org/10.1093/jnci/59.2.435.

    Article  Google Scholar 

  63. McCormick DL, Adamowski CB, Fiks A, Moon RC. Lifetime Dose-Response Relationships for Mammary Tumor Induction by a Single Administration of N-Methyl-N-nitrosourea. Cancer Res. 1981;41:1690–4.

    CAS  PubMed  Google Scholar 

  64. Russo J, Wilgus G, Russo IH. Susceptibility of the mammary gland to carcinogenesis: I Differentiation of the mammary gland as determinant of tumor incidence and type of lesion. Am J Pathol. 1979;96:721–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Russo J, Russo IH. Susceptibility of the mammary gland to carcinogenesis. II. Pregnancy interruption as a risk factor in tumor incidence. Am J Pathol American Society for Investigative Pathology. 1980;100:497–512.

    CAS  Google Scholar 

  66. Sinha DK, Pazik JE, Dao TL. Prevention of mammary carcinogenesis in rats by pregnancy: effect of full-term and interrupted pregnancy. Br J Cancer. 1988;57:390–4. https://doi.org/10.1038/bjc.1988.88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sivaraman L, Conneely OM, Medina D, O’Malley BW. p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis. Proc Natl Acad Sci USA. 2001;98:12379–84. https://doi.org/10.1073/pnas.221459098.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Becker KA, Lu S, Dickinson ES, Dunphy KA, Mathews L, Schneider SS, et al. Estrogen and progesterone regulate radiation-induced p53 activity in mammary epithelium through TGF-beta-dependent pathways. Oncogene. 2005;24:6345–53. https://doi.org/10.1038/sj.onc.1208787.

    Article  CAS  PubMed  Google Scholar 

  69. Jerry DJ, Minter LM, Becker KA, Blackburn AC. Hormonal control of p53 and chemoprevention. Breast cancer Res. 2002;4:91–4. https://doi.org/10.1186/bcr431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sivaraman L, Medina D. Hormone-Induced Protection Against Breast Cancer. J Mammary Gland Biol Neoplasia. 2002;7:77–92. https://doi.org/10.1023/A:1015774524076.

    Article  PubMed  Google Scholar 

  71. Ding L, Zhao Y, Warren CL, Sullivan R, Eliceiri KW, Shull JD. Association of cellular and molecular responses in the rat mammary gland to 17β-estradiol with susceptibility to mammary cancer. BMC Cancer. 2013;13:573. https://doi.org/10.1186/1471-2407-13-573.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Shull JD, Dennison KL, Chack AC, Trentham-Dietz A. Rat models of 17β-estradiol-induced mammary cancer reveal novel insights into breast cancer etiology and prevention. Physiol Genomics. 2018;50:215–34. https://doi.org/10.1152/physiolgenomics.00105.2017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Huggins C, Briziarelli G, Sutton H. Rapid induction of mammary carcinoma in the rat and the influence of hormones on the tumors. J Exp Med. 1959;109:25–42. https://doi.org/10.1084/jem.109.1.25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shull JD, Spady TJ, Snyder MC, Johansson SL, Pennington KL. Ovary-intact, but not ovariectomized female ACI rats treated with 17β-estradiol rapidly develop mammary carcinoma. Carcinogenesis. 1997;18:1595–601. https://doi.org/10.1093/carcin/18.8.1595.

    Article  CAS  PubMed  Google Scholar 

  75. Harvell DME, Strecker TE, Xie B, Pennington KL, McComb RD, Shull JD. Dietary energy restriction inhibits estrogen-induced mammary, but not pituitary, tumorigenesis in the ACI rat. Carcinogenesis. 2002;23:161–9. https://doi.org/10.1093/carcin/23.1.161.

    Article  CAS  PubMed  Google Scholar 

  76. Dunning WF, Curtis MR. The Incidence of Diethylstilbestrol-induced Cancer in Reciprocal F1 Hybrids Obtained from Crosses Between Rats of Inbred Lines That are Susceptible and Resistant to the Induction of Mammary Cancer by This Agent. Cancer Res. 1952;12:702–6.

    CAS  PubMed  Google Scholar 

  77. Harvell DME, Strecker TE, Tochacek M, Xie B, Pennington KL, McComb RD, et al. Rat strain-specific actions of 17β-estradiol in the mammary gland: Correlation between estrogen-induced lobuloalveolar hyperplasia and susceptibility to estrogen-induced mammary cancers. Proc Natl Acad Sci USA. 2000;97:2779–84. https://doi.org/10.1073/pnas.050569097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Gould KA, Tochacek M, Schaffer BS, Reindl TM, Murrin CR, Lachel CM, et al. Genetic determination of susceptibility to estrogen-induced mammary cancer in the ACI rat: Mapping of Emca1 and Emca2 to chromosomes 5 and 18. Genetics. 2004;168:2113–25. https://doi.org/10.1534/genetics.104.033878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shull JD, Lachel CM, Murrin CR, Pennington KL, Schaffer BS, Strecker TE, et al. Genetic control of estrogen action in the rat: Mapping of QTLs that impact pituitary lactotroph hyperplasia in a BN x ACI intercross. Mamm Genome. 2007;18:657–69. https://doi.org/10.1007/s00335-007-9052-2.

    Article  CAS  PubMed  Google Scholar 

  80. Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R. ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015;12:573–83. https://doi.org/10.1038/nrclinonc.2015.117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Fisher B, Costantino JP, Wickerham DL, Cecchini RS, Cronin WM, Robidoux A, et al. Tamoxifen for the prevention of breast cancer: Current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005;97:1652–62. https://doi.org/10.1093/jnci/dji372.

    Article  CAS  PubMed  Google Scholar 

  82. Jordan VC. Effect of tamoxifen (ICI 46,474) on initiation and growth of DMBA-induced rat mammary carcinomata. Eur J Cancer. 1976;12:419–24. https://doi.org/10.1016/0014-2964(76)90030-X.

    Article  CAS  PubMed  Google Scholar 

  83. Turan VK, Sanchez RI, Li JJ, Li SA, Reuhl KR, Thomas PE, et al. The effects of steroidal estrogens in ACI rat mammary carcinogenesis: 17β-estradiol, 2-hydroxyestradiol, 4-hydroxyestradiol, 16α-hydroxyestradiol, and 4-hydroxyestrone. J Endocrinol. 2004;183:91–9. https://doi.org/10.1677/joe.1.05802.

    Article  CAS  PubMed  Google Scholar 

  84. El-Bayoumy K, Ji BY, Upadhyaya P, Chae YH, Kurtzke C, Rivenson A, et al. Lack of tumorigenicity of cholesterol epoxides and estrone-3,4-quinone in the rat mammary gland. Cancer Res. 1996;56:1970–3.

    CAS  PubMed  Google Scholar 

  85. Dwivedy I, Devanesan P, Cremonesi P, Rogan E, Cavalieri E. Synthesis and Characterization of Estrogen 2,3-and 3,4-Quinones. Comparison of DNA Adducts Formed by the Quinones versus Horseradish Peroxidase-Activated Catechol Estrogens. Chem Res Toxicol. 1992;5:828–33. https://doi.org/10.1021/tx00030a016.

    Article  CAS  PubMed  Google Scholar 

  86. Cavalieri EL, Rogan EG. Depurinating estrogen-DNA adducts in the etiology and prevention of breast and other human cancers. Futur Oncol. 2010;6:75–91. https://doi.org/10.2217/fon.09.137.

    Article  CAS  Google Scholar 

  87. Cavalieri EL, Rogan EG. Depurinating estrogen-DNA adducts, generators of cancer initiation: their minimization leads to cancer prevention. Clin Transl Med. 2016;5:12. https://doi.org/10.1186/s40169-016-0088-3.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Adamovic T, Roshani L, Chen L, Schaffer BS, Helou K, Levan G, et al. Nonrandom pattern of chromosome aberrations in 17β-estradiol-induced rat mammary tumors: Indications of distinct pathways for tumor development. Genes Chromosom Cancer. 2007;46:459–69. https://doi.org/10.1002/gcc.20428.

    Article  CAS  PubMed  Google Scholar 

  89. Jacob HJ. Modern genetic mapping approaches in laboratory animals/rats. J Exp Anim Sci. 2000;41:32–4.

    Article  Google Scholar 

  90. Li JJ, Papa D, Davis MF, Weroha SJ, Aldaz CM, El-Bayoumy K, et al. Ploidy differences between hormone- and chemical carcinogen-induced rat mammary neoplasms: Comparison to invasive human ductal breast cancer. Mol Carcinog. 2002;33:56–65. https://doi.org/10.1002/mc.10022.

    Article  CAS  PubMed  Google Scholar 

  91. Christian AT, Snyderwine EG, Tucker JD. Comparative genomic hybridization analysis of PhIP-induced mammary carcinomas in rats reveals a cytogenetic signature. Mutat Res. 2002;506–507:113–9. https://doi.org/10.1016/S0027-5107(02)00157-4.

    Article  PubMed  Google Scholar 

  92. Samuelson E, Karlsson S, Partheen K, Nilsson S, Szpirer C, Behboudi A. BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors. BMC Cancer. 2012;12:352. https://doi.org/10.1186/1471-2407-12-352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Adamovic T, McAllister D, Guryev V, Wang X, Andrae JW, Cuppen E, et al. Microalterations of Inherently Unstable Genomic Regions in Rat Mammary Carcinomas as Revealed by Long Oligonucleotide Array-Based Comparative Genomic Hybridization. Cancer Res. 2009;69:5159–67. https://doi.org/10.1158/0008-5472.CAN-08-4038.

    Article  CAS  PubMed  Google Scholar 

  94. Jiang S, Katayama H, Wang J, Li SA, Hong Y, Radvanyi L, et al. Estrogen-Induced Aurora Kinase-A (AURKA) Gene Expression is Activated by GATA-3 in Estrogen Receptor-Positive Breast Cancer Cells. Horm Cancer. 2010;1:11–20. https://doi.org/10.1007/s12672-010-0006-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Li JJ, Weroha SJ, Lingle WL, Papa D, Salisbury JL, Li SA. Estrogen mediates Aurora-A overexpression, centrosome amplification, chromosomal instability, and breast cancer in female ACI rats. Proc Natl Acad Sci USA. 2004;101:18123–8. https://doi.org/10.1073/pnas.0408273101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lee HH, Zhu Y, Govindasamy KM, Gopalan G. Downregulation of Aurora-A overrides estrogen-mediated growth and chemoresistance in breast cancer cells. Endocr Relat Cancer. 2008;15:765–75. https://doi.org/10.1677/ERC-07-0213.

    Article  CAS  PubMed  Google Scholar 

  97. Zhou H, Kuang J, Zhong L, Kuo W, Gray JW, Sahin A, et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet. 1998;20:189–93. https://doi.org/10.1038/2496.

    Article  CAS  PubMed  Google Scholar 

  98. Fussell KC, Udasin RG, Smith PJS, Gallo MA, Laskin JD. Catechol metabolites of endogenous estrogens induce redox cycling and generate reactive oxygen species in breast epithelial cells. Carcinogenesis. 2011;32:1285–93. https://doi.org/10.1093/carcin/bgr109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Petrek JA, Sandberg WA, Cole MN, Silberman MS, Collins DC. The inhibitory effect of caffeine on hormone-induced rat breast cancer. Cancer. 1985;56:1977–81. https://doi.org/10.1002/1097-0142(19851015)56:8%3C1977::AID-CNCR2820560815%3E3.0.CO;2-7.

    Article  CAS  PubMed  Google Scholar 

  100. Holtzman S. Retinyl acetate inhibits estrogen-induced mammary carcinogenesis in female ACI rats. Carcinogenesis. 1988;9:305–7. https://doi.org/10.1093/carcin/9.2.305.

    Article  CAS  PubMed  Google Scholar 

  101. Noble RL, Cutts JH. Mammary Tumors of the Rat: A Review. Cancer Res. 1959;19:1125–39.

    CAS  PubMed  Google Scholar 

  102. Ruhlen RL, Willbrand DM, Besch-Williford CL, Ma L, Shull JD, Sauter ER. Tamoxifen induces regression of estradiol-induced mammary cancer in ACI.COP-Ept2 rat model. Breast Cancer Res Treat. 2009;117:517–24. https://doi.org/10.1007/s10549-008-0169-0.

    Article  CAS  PubMed  Google Scholar 

  103. Geschickter CF. Estrogenic Mammary Cancer in the Rat. Radiology. 1939;33:439–49. https://doi.org/10.1148/33.4.439.

    Article  Google Scholar 

  104. Geschickter CF, Byrnes EW. Factors Influencing the Development and Time of Appearance of Mammary Cancer in the Rat in Response to Estrogens. Arch Pathol. 1942;33:334–56.

    CAS  Google Scholar 

  105. Soffriti M, Minardi F, Maltoni C. Known Physical Carcinogens. In: Kufe D, Pollock R, Weichselbaum R, editors. Holland-Frei Cancer Med [Internet]. 6th ed. Hamilton (ON): BC Decker; 2003. Available from: https://www.ncbi.nlm.nih.gov/books/NBK13421/.

  106. Berkel H, Birdsell DC, Jenkins H. Breast Augmentation: A Risk Factor for Breast Cancer? N Engl J Med. 1992;326:1649–53. https://doi.org/10.1056/NEJM199206183262501.

    Article  CAS  PubMed  Google Scholar 

  107. Bryson G, Bischoff F. Silicate-induced neoplasms. Prog Exp Tumor Res. 1967;9:77–164.

    Article  CAS  PubMed  Google Scholar 

  108. Institute of Medicine (US) Committee on the Safety of Silicone Breast. Safety of Silicone Breast Implants. Bondurant S, Ernster V, Herdman R, editors. Washington (DC): National Academies Press (US); 1999.

    Google Scholar 

  109. Brand KG, Brand I. Risk assessment of carcinogenesis at implantation sites. Plast Reconstr Surg. 1980;66:591–5. https://doi.org/10.1097/00006534-198010000-00015.

    Article  CAS  PubMed  Google Scholar 

  110. Su CW, Dreyfuss DA, Krizek TJ, Leoni KJ. Silicone implants and the inhibition of cancer. Plast Reconstr Surg. 1995;96:513–8. https://doi.org/10.1097/00006534-199509000-00001.

    Article  CAS  PubMed  Google Scholar 

  111. Mclaughlin JK, Fraumeni JF, Nyren O, Adami HO. Silicone breast implants and risk of cancer? JAMA. 1995;273:116. https://doi.org/10.1001/jama.1995.03520260036028.

    Article  CAS  PubMed  Google Scholar 

  112. Brinton LA, Brown SL. Breast Implants and Cancer. J Natl Cancer Inst. 1997;89:1341–9. https://doi.org/10.1093/jnci/89.18.1341.

    Article  CAS  PubMed  Google Scholar 

  113. Herrera VL, Ponce LR, Ruiz-Opazo N. Multiple Susceptibility Loci for Radiation-Induced Mammary Tumorigenesis in F2[Dahl S x R]-Intercross Rats. PLoS ONE. 2013;8:e72143. https://doi.org/10.1371/journal.pone.0072143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lee H, Lee Y, Kang C, Bae S, Jeoung D, Jang J, et al. Differential Gene Signatures in Rat Mammary Tumors Induced by DMBA and Those Induced by Fractionated γ Radiation. Radiat Res. 2008;170:579–90. https://doi.org/10.1667/RR1106.1.

    Article  CAS  PubMed  Google Scholar 

  115. Moriyama H, Daino K, Ishikawa A, Imaoko T, Nishimura M, NISHIMURA Y, et al. Exome of radiation-induced rat mammary carcinoma shows copy-number losses and mutations in human-relevant cancer genes. Anticancer Res. 2021;41:55–70. https://doi.org/10.21873/anticanres.14751.

    Article  CAS  PubMed  Google Scholar 

  116. Inano H, Onoda M. Prevention of radiation-induced mammary tumors. Int J Radiat Oncol. 2002;52:212–23. https://doi.org/10.1016/S0360-3016(01)02651-7.

    Article  Google Scholar 

  117. Takabatake M, Daino K, Imaoka T, Blyth BJ, Kokubo T, Nishimura Y, et al. Differential effect of parity on rat mammary carcinogenesis after pre- or post-pubertal exposure to radiation. Sci Rep. 2018;8:14325. https://doi.org/10.1038/s41598-018-32406-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Imaoka T, Nishimura M, Kakinuma S, Hatano Y, Ohmachi Y, Yoshinaga S, et al. High Relative Biologic Effectiveness of Carbon Ion Radiation on Induction of Rat Mammary Carcinoma and its Lack of H-ras and Tp53 Mutations. Int J Radiat Oncol. 2007;69:194–203. https://doi.org/10.1016/j.ijrobp.2007.05.026.

    Article  CAS  Google Scholar 

  119. Bond VP, Shellabarger CJ, Cronkite EP, Fliedner TM. Studies on radiation-induced mammary gland neoplasia in the rat. V. Induction by localized irradiation. Radiat Res. 1960;13:318–28. https://doi.org/10.2307/3570964.

    Article  CAS  PubMed  Google Scholar 

  120. Imaoka T, Nishimura M, Iizuka D, Daino K, Takabatake T, Okamoto M, et al. Radiation-Induced Mammary Carcinogenesis in Rodent Models: What’s Different from Chemical Carcinogenesis? J Radiat Res. 2009;50:281–93. https://doi.org/10.1269/jrr.09027.

    Article  CAS  PubMed  Google Scholar 

  121. Huggins C, Fukunishi R. Cancer in the Rat after Single Exposures to Irradiation or Hydrocarbons: Age and Strain Factors. Hormone Dependence of the Mammary Cancers. Radiat Res. 1963;20:493–503. https://doi.org/10.2307/3571380.

    Article  CAS  PubMed  Google Scholar 

  122. Dicello JF, Christian A, Cucinotta FA, Gridley DS, Kathirithamby R, Mann J, et al. In vivo mammary tumourigenesis in the Sprague-Dawley rat and microdosimetric correlates. Phys Med Biol. 2004;49:3817. https://doi.org/10.1088/0031-9155/49/16/024.

    Article  CAS  PubMed  Google Scholar 

  123. Broerse JJ, Hennen LA, Klapwijk WM, Solleveld HA. Mammary carcinogenesis in different rat strains after irradiation and hormone administration. Int J Radiat Biol Relat Stud Phys Chem Med. 1987;51:1091–100. https://doi.org/10.1080/09553008714551381.

    Article  CAS  PubMed  Google Scholar 

  124. Nishimura M, Daino K, Fukuda M, Tanaka I, Moriyama H, Showler K, et al. Development of mammary cancer in γ-irradiated F1 hybrids of susceptible Sprague-Dawley and resistant Copenhagen rats, with copy-number losses that pinpoint potential tumor suppressors. PLoS ONE. 2021;16:e0255968. https://doi.org/10.1371/journal.pone.0255968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Bond VP, Cronkite EP, Lippincott SW, Shellabarger CJ. Studies on radiation-induced mammary gland neoplasia in the rat. III. Relation of the neoplastic response to dose of total-body radiation. Radiat Res. 1960;12:276–85. https://doi.org/10.2307/3570916.

    Article  CAS  PubMed  Google Scholar 

  126. Borrego-Soto G, Ortiz-López R, Rojas-Martínez A. Ionizing radiation-induced DNA injury and damage detection in patients with breast cancer. Genet Mol Biol. 2015;38:420–32. https://doi.org/10.1590/s1415-475738420150019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Haag JD, Hsu LC, Newton MA, Gould MN. Allelic imbalance in mammary carcinomas induced by either 7,12-dimethylbenz[a]anthracene or ionizing radiation in rats carrying genes conferring differential susceptibilities to mammary carcinogenesis. Mol Carcinog. 1996;17(199611):134–43. https://doi.org/10.1002/(SICI)1098-2744. ()17:3%3C134 :AID-MC5%3E3.0.CO;2-F.

    Article  CAS  PubMed  Google Scholar 

  128. Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart MJ, et al. Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 2015;26:1533–46. https://doi.org/10.1093/annonc/mdv221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Imaoka T, Nishimura M, Nishimura Y, Kakinuma S, Shimada Y. Persistent Cell Proliferation of Terminal End Buds Precedes Radiation-induced Rat Mammary Carcinogenesis. Vivo. 2006;20:353–8.

    Google Scholar 

  130. Bartstra RW, Bentvelzen PAJ, Zoetelief J, Mulder AH, Broerse JJ, Van Bekkum DW. Induction of mammary tumors in rats by single-dose gamma irradiation at different ages. Radiat Res. 1998;150:442–50. https://doi.org/10.2307/3579664.

    Article  CAS  PubMed  Google Scholar 

  131. Solleveld HA, van Zwieten MJ, Broerse JJ, Hollander CF. Effects of X-irradiation, ovariohysterectomy and estradiol-17β on incidence, benign/malignant ratio and multiplicity of rat mammary neoplasms—A preliminary report. Leuk Res. 1986;10:755–9. https://doi.org/10.1016/0145-2126(86)90292-4.

    Article  CAS  PubMed  Google Scholar 

  132. Hollingsworth AB, Lerner MR, Lightfoot SA, Wilkerson KB, Hanas JS, McCay PB, et al. Prevention of DMBA-induced rat mammary carcinomas comparing leuprolide, oophorectomy, and tamoxifen. Breast Cancer Res Treat. 1998;47:63–70. https://doi.org/10.1023/a:1005872132373.

    Article  CAS  PubMed  Google Scholar 

  133. Mucci LA, Hjelmborg JB, Harris JR, Czene K, Havelick DJ, Scheike T, et al. Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. JAMA. 2016;315:68–76. https://doi.org/10.1001/jama.2015.17703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343:78–85. https://doi.org/10.1056/nejm200007133430201.

    Article  CAS  PubMed  Google Scholar 

  135. Wendt C, Margolin S. Identifying breast cancer susceptibility genes - a review of the genetic background in familial breast cancer. Acta Oncol (Madr). 2019;58:135–46. https://doi.org/10.1080/0284186x.2018.1529428.

    Article  CAS  Google Scholar 

  136. Shellabarger CJ, Stone JP, Holtzman S. Rat Differences in Mammary Tumor Induction With Estrogen and Neutron Radiation. J Natl Cancer Inst. 1978;61:1505–8.

    CAS  PubMed  Google Scholar 

  137. Hsu LC, Kennan WS, Shepel LA, Jacob HJ, Szpirer C, Szpirer J, et al. Genetic Identification of Mcs-1, a Rat Mammary Carcinoma Suppressor Gene. Cancer Res. 1994;54:2765–70.

    CAS  PubMed  Google Scholar 

  138. Shepel LA, Lan H, Haag JD, Brasic GM, Gheen ME, Simon JS, et al. Genetic Identification of Multiple Loci That Control Breast Cancer Susceptibility in the Rat. Genetics. 1998;149:289–99. https://doi.org/10.1093/genetics/149.1.289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Schaffer BS, Lachel CM, Pennington KL, Murrin CR, Strecker TE, Tochacek M, et al. 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. 2006;66:7793–800. https://doi.org/10.1158/0008-5472.can-06-0143.

    Article  CAS  PubMed  Google Scholar 

  140. Lan H, Kendziorski CM, Haag JD, Shepel LA, Newton MA, Gould MN. Genetic loci controlling breast cancer susceptibility in the Wistar-Kyoto rat. Genetics. 2001;157:331–9. https://doi.org/10.1093/genetics/157.1.331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Quan X, Laes JF, Stieber D, Rivière M, Russo J, Wedekind D, et al. Genetic identification of distinct loci controlling mammary tumor multiplicity, latency, and aggressiveness in the rat. Mamm Genome. 2006;17:310–21. https://doi.org/10.1007/s00335-005-0125-9.

    Article  CAS  PubMed  Google Scholar 

  142. Silver LM. 3.2 Mouse Crosses and Standard Strains. Mouse Genet Concepts Appl [Internet]. New York, NY: Oxford University Press; 1995. Available from: http://www.informatics.jax.org/silver/chapters/3-2.shtml.

  143. Johnson KR, Zheng QY, Noben-Trauth K. Strain background effects and genetic modifiers of hearing in mice. Brain Res. 2006;1091:79–88. https://doi.org/10.1016/j.brainres.2006.02.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Darvasi A. Experimental strategies for the genetic dissection of complex traits in animal models. Nat Genet. 1998;18:19–24. https://doi.org/10.1038/ng0198-19.

    Article  CAS  PubMed  Google Scholar 

  145. Da Y, Garbe J, London N, Xu J. Linkage analysis using direct and indirect counting and relative efficiencies for codominant and dominant loci. J Anim Sci. 2002;80:2528–39. https://doi.org/10.2527/2002.80102528x.

    Article  CAS  PubMed  Google Scholar 

  146. Silver LM. 9.4 Starting from Scratch with a New Mapping Project. Mouse Genet Concepts Appl [Internet]. New York, NY: Oxford University Press; 1995. Available from: http://www.informatics.jax.org/silver/chapters/9-4.shtml.

  147. Samuelson DJ, Hesselson SE, Aperavich BA, Zan Y, Haag JD, Trentham-Dietz A, et al. Rat Mcs5a is a compound quantitative trait locus with orthologous human loci that associate with breast cancer risk. Proc Natl Acad Sci USA. 2007;104:6299–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Cotroneo MS, Merry GM, Haag JD, Lan H, Shepel LA, Gould MN. The Mcs7 quantitative trait locus is associated with an increased susceptibility to mammary cancer in congenic rats and an allele-specific imbalance. Oncogene. 2006;25:5011–7. https://doi.org/10.1038/sj.onc.1209506.

    Article  CAS  PubMed  Google Scholar 

  149. Haag JD, Shepel LA, Kolman BD, Monson DM, Benton ME, Watts KT, et al. Congenic rats reveal three independent Copenhagen alleles within the Mcs1 quantitative trait locus that confer resistance to mammary cancer. Cancer Res. 2003;63:5808–12.

    CAS  PubMed  Google Scholar 

  150. Le S, Martin ZC, Samuelson DJ. Physical confirmation and comparative genomics of the rat Mammary carcinoma susceptibility 3 quantitative trait locus. G3 Genes. Genomes Genet. 2017;7:1767–73. https://doi.org/10.1534/g3.117.039388.

    Article  CAS  Google Scholar 

  151. Shao H, Sinasac DS, Burrage LC, Hodges CA, Supelak PJ, Palmert MR, et al. Analyzing complex traits with congenic strains. Mamm Genome. 2010;21:276–86. https://doi.org/10.1007/s00335-010-9267-5.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Markel P, Shu P, Ebeling C, Carlson GA, Nagle DL, Smutko JS, et al. Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains. Nat Genet. 1997;17:280–4. https://doi.org/10.1038/ng1197-280.

    Article  CAS  PubMed  Google Scholar 

  153. Wakeland E, Morel L, Achey K, Yui M, Longmate J. Speed congenics: a classic technique in the fast lane (relatively speaking). Immunol Today. 1997;18:472–7. https://doi.org/10.1016/S0167-5699(97)01126-2.

    Article  CAS  PubMed  Google Scholar 

  154. Ren X, Graham JC, Jing L, Mikheev AM, Gao Y, Lew JP, et al. Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus (QTL30) on rat chromosome 12: identification of fry as a candidate Mcs gene. PLoS ONE. 2013;8:e70930. https://doi.org/10.1371/journal.pone.0070930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Samuelson DJ, Aperavich BA, Haag JD, Gould MN. Fine mapping reveals multiple loci and a possible epistatic interaction within the mammary carcinoma susceptibility quantitative trait locus, Mcs5. Cancer Res. 2005;65:9637–42. https://doi.org/10.1158/0008-5472.can-05-1498.

    Article  CAS  PubMed  Google Scholar 

  156. Schaffer BS, Leland-Wavrin KM, Kurz SG, Colletti JA, Seiler NL, Warren CL, et al. Mapping of three genetic determinants of susceptibility to estrogen-induced mammary cancer within the Emca8 Locus on rat chromosome 5. Cancer Prev Res. 2013;6:59–69. https://doi.org/10.1158/1940-6207.CAPR-12-0346-T.

    Article  CAS  Google Scholar 

  157. Sanders J, Samuelson DJ. Significant overlap between human genome-wide association-study nominated breast cancer risk alleles and rat mammary cancer susceptibility loci. Breast Cancer Res. 2014;16:R14. https://doi.org/10.1186/bcr3607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  159. Adamovic T, Mcallister D, Wang T, Adamovic D, Rowe JJ, Moreno C, et al. Identification of Novel Carcinogen-mediated Mammary Tumor Susceptibility Loci in the Rat Using the Chromosome Substitution Technique. Genes Chromosom Cancer. 2010;49:1035–45. https://doi.org/10.1002/gcc.20812.

    Article  CAS  PubMed  Google Scholar 

  160. Colletti JA, Leland-Wavrin KM, Kurz SG, Hickman MP, Seiler NL, Samanas NB, et al. Validation of six genetic determinants of susceptibility to estrogen-induced mammary cancer in the rat and assessment of their relevance to breast cancer risk in humans. G3 Genes. Genomes Genet. 2014;4:1385–94. https://doi.org/10.1534/g3.114.011163.

    Article  CAS  Google Scholar 

  161. Korkola JE, Archer MC. Resistance to mammary tumorigenesis in Copenhagen rats is associated with the loss of preneoplastic lesions. Carcinogenesis. 1999;20:221–7. https://doi.org/10.1093/carcin/20.2.221.

    Article  CAS  PubMed  Google Scholar 

  162. Korkola JE, Wood GA, Archer MC. Cyclin D1 expression during rat mammary tumor development and its potential role in the resistance of the Copenhagen rat. Breast Cancer Res. 1999;1:88. https://doi.org/10.1186/bcr18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Lu SJ, Archer MC. Ha-ras oncogene activation in mammary glands of N-methyl-N-nitrosourea- treated rats genetically resistant to mammary adenocarcinogenesis. Proc Natl Acad Sci USA. 1992;89:1001–5. https://doi.org/10.1073/pnas.89.3.1001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Stone JP, Holtzman S, Shellabarger CJ. Neoplastic Responses and Correlated Plasma Prolactin Levels in Diethylstilbestrol-Treated ACI and Sprague-Dawley Rats. Cancer Res. 1979;39:773–8.

    CAS  PubMed  Google Scholar 

  165. Meites J. Relation of Prolactin and Estrogen to Mammary Tumorigenesis in the Rat. J Natl Cancer Inst. 1972;48:1217–24. https://doi.org/10.1093/jnci/48.4.1217.

    Article  CAS  PubMed  Google Scholar 

  166. Spady TJ, Harvell DME, Snyder MC, Pennington KL, McComb RD, Shull JD. Estrogen-induced tumorigenesis in the Copenhagen rat: disparate susceptibilities to development of prolactin-producing pituitary tumors and mammary carcinomas. Cancer Lett. 1998;124:95–103. https://doi.org/10.1016/s0304-3835(97)00455-2.

    Article  CAS  PubMed  Google Scholar 

  167. Ren X, Zhang X, Kim AS, Mikheev AM, Fang M, Sullivan RC, et al. Comparative genomics of susceptibility to mammary carcinogenesis among inbred rat strains: role of reduced prolactin signaling in resistance of the Copenhagen strain. Carcinogenesis. 2008;29:177–85. https://doi.org/10.1093/carcin/bgm224.

    Article  CAS  PubMed  Google Scholar 

  168. Zukerberg LR, Yang WI, Gadd M, Thor AD, Koerner FC, Schmidt EV, et al. Cyclin D1 (PRAD1) protein expression in breast cancer: Approximately one-third of infiltrating mammary carcinomas show overexpression of the cyclin D1 oncogene. Mod Pathol. 1995;8:560–7.

    CAS  PubMed  Google Scholar 

  169. Bartkova J, Lukas J, Müller H, Lützhøt D, Strauss M, Bartek J. Cyclin D1 protein expression and function in human breast cancer. Int J Cancer. 1994;57:353–61. https://doi.org/10.1002/ijc.2910570311.

    Article  CAS  PubMed  Google Scholar 

  170. Buckley MF, Sweeney KJE, Hamilton JA, Sini RL, Manning DL, Nicholson RI, et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene. 1993;8:2127–33.

    CAS  PubMed  Google Scholar 

  171. Montalto FI, De Amicis F. Cyclin D1 in Cancer: A Molecular Connection for Cell Cycle Control, Adhesion and Invasion in Tumor and Stroma. Cells. 2020;9:2648. https://doi.org/10.3390/cells9122648.

    Article  CAS  PubMed Central  Google Scholar 

  172. Ashrafi M, Bathaie SZ, Abroun S. High Expression of Cyclin D1 and p21 in N-Nitroso-N-Methylurea-Induced Breast Cancer in Wistar Albino Female Rats. Cell J. 2012;14:193–202.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Weroha JS, Li SA, Tawfik O, Li JJ. Overexpression of cyclins D1 and D3 during estrogen-induced breast oncogenesis in female ACI rats. Carcinogenesis. 2006;27:491–8. https://doi.org/10.1093/carcin/bgi278.

    Article  CAS  PubMed  Google Scholar 

  174. Li YJ, Song R, Korkola JE, Archer MC, Ben-David Y. Cyclin D1 is necessary but not sufficient for anchorage-independent growth of rat mammary tumor cells and is associated with resistance of the Copenhagen rat to mammary carcinogenesis. Oncogene. 2003;22:3452–62. https://doi.org/10.1038/sj.onc.1206411.

    Article  CAS  PubMed  Google Scholar 

  175. Isaacs JT. Inheritance of a Genetic Factor from the Copenhagen Rat and the Suppression of Chemically Induced Mammary Adenocarcinogenesis. Cancer Res. 1988;48:2204–13.

    CAS  PubMed  Google Scholar 

  176. Lella V, Stieber D, Rivière M, Szpirer J, Szpirer C. Mammary cancer resistance and precocious mammary differentiation in the WKY rat: Identification of 2 quantitative trait loci. Int J Cancer. 2007;121:1738–43. https://doi.org/10.1002/ijc.22924.

    Article  CAS  PubMed  Google Scholar 

  177. Henning AN, Haag JD, Smits BMG, Gould MN. The Non-coding Mammary Carcinoma Susceptibility Locus, Mcs5c, Regulates Pappa Expression via Age-Specific Chromatin Folding and Allele-Dependent DNA Methylation. PLoS Genet. 2016;12:e1006261. https://doi.org/10.1371/journal.pgen.1006261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Conover CA, Bale LK, Overgaard MT, Johnstone EW, Laursen UL, Füchtbauer EM, et al. Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development. Development. 2004;131:1187–94. https://doi.org/10.1242/dev.00997.

    Article  CAS  PubMed  Google Scholar 

  179. Christopoulos PF, Msaouel P, Koutsilieris M. The role of the insulin-like growth factor-1 system in breast cancer. Mol Cancer. 2015;14:43. https://doi.org/10.1186/s12943-015-0291-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Smits BMG, Sharma D, Samuelson DJ, Woditschka S, Mau B, Haag JD, et al. The non-protein coding breast cancer susceptibility locus Mcs5a acts in a non-mammary cell-autonomous fashion through the immune system and modulates T-cell homeostasis and functions. Breast Cancer Res. 2011;13:R81. https://doi.org/10.1186/bcr2933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Pauza CD, Liou ML, Lahusen T, Xiao L, Lapidus RG, Cairo C, et al. Gamma delta T cell therapy for cancer: It is good to be local. Front Immunol. 2018;9:1305. https://doi.org/10.3389/fimmu.2018.01305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Devapatla B, Sanders J, Samuelson DJ. Genetically determined inflammatory-response related cytokine and chemokine transcript profiles between mammary carcinoma resistant and susceptible rat strains. Cytokine. 2012;59:223–7. https://doi.org/10.1016/j.cyto.2012.04.037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Zhao W, Grubbs CJ, Myers RK, Nilsen-Hamilton M. Parity is associated with an expanded macrophage population in the mammary gland. Int J Oncol. 2010;37:1195–202. https://doi.org/10.3892/ijo_00000771.

    Article  CAS  PubMed  Google Scholar 

  184. Kouros-Mehr H, Kim J, Bechis SK, Werb Z. GATA-3 and the regulation of the mammary luminal cell fate. Curr Opin Cell Biol. 2008;20:164–70. https://doi.org/10.1016/j.ceb.2008.02.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Rajaram RD, Buric D, Caikovski M, Ayyanan A, Rougemont J, Shan J, et al. Progesterone and Wnt4 control mammary stem cells via myoepithelial crosstalk. EMBO J. 2015;34:641–52. https://doi.org/10.15252/embj.201490434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell. 2000;103:41–50. https://doi.org/10.1016/s0092-8674(00)00103-3.

    Article  CAS  PubMed  Google Scholar 

  187. Smits BMG, Haag JD, Rissman AI, Sharma D, Tran A, Schoenborn AA, et al. The Gene Desert Mammary Carcinoma Susceptibility Locus Mcs1a Regulates Nr2f1 Modifying Mammary Epithelial Cell Differentiation and Proliferation. PLoS Genet. 2013;9:e1003549. https://doi.org/10.1371/journal.pgen.1003549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Veillet AL, Haag JD, Remfert JL, Meilahn AL, Samuelson DJ, Gould MN. Mcs5c: A mammary carcinoma susceptibility locus located in a gene desert that associates with tenascin c expression. Cancer Prev Res. 2011;4:97–106. https://doi.org/10.1158/1940-6207.capr-10-0187.

    Article  CAS  Google Scholar 

  189. DenDekker AD, Xu X, Vaughn MD, Puckett AH, Gardner LL, Lambring CJ, et al. Rat Mcs1b is concordant to the genome-wide association-identified breast cancer risk locus at human 5q11.2 and MIER3 is a candidate cancer susceptibility gene. Cancer Res. 2012;72:6002–12. https://doi.org/10.1158/0008-5472.can-12-0748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Ferreira MA, Gamazon ER, Al-Ejeh F, Aittomäki K, Andrulis IL, Anton-Culver H, et al. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer. Nat Commun. 2019;10:1741. https://doi.org/10.1038/s41467-018-08053-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Zhang H, Ahearn TU, Lecarpentier J, Barnes D, Beesley J, Qi G, et al. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. Nat Genet. 2020;52:572–81. https://doi.org/10.1038/s41588-020-0609-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Feng H, Gusev A, Pasaniuc B, Wu L, Long J, Abu-full Z, et al. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status. Genet Epidemiol. 2020;44:442–68. https://doi.org/10.1002/gepi.22288.

    Article  PubMed  PubMed Central  Google Scholar 

  193. O’Brien J, Hayder H, Zayed Y, Peng C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol. 2018;9:1–12. https://doi.org/10.3389/fendo.2018.00402.

    Article  Google Scholar 

  194. Kim YK, Kim VN. Processing of intronic microRNAs. EMBO J. 2007;26:775–83. https://doi.org/10.1038/sj.emboj.7601512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. MacFarlane L-A, Murphy R. P. MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics. 2010;11:537–61. https://doi.org/10.2174/138920210793175895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Yu RMC, Cheah YK. The roles of miRNAs in human breast cancer and canine mammary tumor. Appl Cancer Res. 2017;37:37. https://doi.org/10.1186/s41241-017-0043-7.

    Article  Google Scholar 

  197. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002;99:15524–9. https://doi.org/10.1073/pnas.242606799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Negrini M, Calin GA. Breast cancer metastasis: A microRNA story. Breast Cancer Res. 2008;10:203. https://doi.org/10.1186/bcr1867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Ma XP, Zhang T, Peng B, Yu L, Jiang DK. Association between microRNA Polymorphisms and Cancer Risk Based on the Findings of 66 Case-Control Studies. PLoS ONE. 2013;8:e79584. https://doi.org/10.1371/journal.pone.0079584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Qi P, Wang L, Zhou B, Yao W, Xu S, Zhou Y, et al. Associations of miRNA polymorphisms and expression levels with breast cancer risk in the Chinese population. Genet Mol Res. 2015;14:6289–96. https://doi.org/10.4238/2015.june.11.2.

    Article  CAS  PubMed  Google Scholar 

  201. Bahreini F, Rayzan E, Rezaei N. microRNA-related single-nucleotide polymorphisms and breast cancer. J Cell Physiol. 2021;236:1593–605. https://doi.org/10.1002/jcp.29966.

    Article  CAS  PubMed  Google Scholar 

  202. Nicoloso MS, Sun H, Spizzo R, Kim H, Wickramasinghe P, Shimizu M, et al. Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility. Cancer Res. 2010;70:2789–98. https://doi.org/10.1158/0008-5472.CAN-09-3541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Yanes T, Young MA, Meiser B, James PA. Clinical applications of polygenic breast cancer risk: A critical review and perspectives of an emerging field. Breast Cancer Res. 2020;22:21. https://doi.org/10.1186/s13058-020-01260-3.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Sawyer S, Mitchell G, McKinley J, Chenevix-Trench G, Beesley J, Qing Chen X, et al. A Role for Common Genomic Variants in the Assessment of Familial Breast Cancer. J Clin Oncol. 2012;30:4330–6. https://doi.org/10.1200/jco.2012.41.7469.

    Article  PubMed  Google Scholar 

  205. Läll K, Lepamets M, Palover M, Esko T, Metspalu A, Tõnisson N, et al. Polygenic prediction of breast cancer: Comparison of genetic predictors and implications for risk stratification. BMC Cancer. 2019;19:557. https://doi.org/10.1186/s12885-019-5783-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Woolcott CG, Maskarinec G, Haiman CA, Verheus M, Pagano IS, Le Marchand L, et al. Association between breast cancer susceptibility loci and mammographic density: The Multiethnic Cohort. Breast Cancer Res. 2009;11:R10. https://doi.org/10.1186/bcr2229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Fernandez-Navarro P, Pita G, Santamariña C, Moreno MP, Vidal C, Miranda-García J, et al. Association analysis between breast cancer genetic variants and mammographic density in a large population-based study (Determinants of Density in Mammographies in Spain) identifies susceptibility loci in TOX3 gene. Eur J Cancer. 2013;49:474–81. https://doi.org/10.1016/j.ejca.2012.08.026.

    Article  CAS  PubMed  Google Scholar 

  208. Greenwood CM, Paterson AD, Linton L, Andrulis IL, Apicella C, Dimitromanolakis A, et al. A genome-wide linkage study of mammographic density, a risk factor for breast cancer. Breast Cancer Res. 2011;13:R132. https://doi.org/10.1186/bcr3078.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Vachon CM, Scott CG, Fasching PA, Hall P, Tamimi RM, Li J, et al. Common breast cancer susceptibility variants in LSP1 and RAD51L1 are associated with mammographic density measures that predict breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2012;21:1156–66. https://doi.org/10.1158/1055-9965.epi-12-0066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Hunter DJ, Kraft P, Jacobs KB, Cox DG, Yeager M, Hankinson SE, et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat Genet. 2007;39:870–4. https://doi.org/10.1038/ng2075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Campbel TM, Castro MAA, De Santiago I, Fletcher MNC, Halim S, Prathalingam R, et al. FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness. Carcinogenesis. 2016;37:741–50. https://doi.org/10.1093/carcin/bgw065.

    Article  CAS  Google Scholar 

  212. Gould MN. The utility of comparative genetics to inform breast cancer prevention strategies. Genetics. 2009;183:409–12. https://doi.org/10.1534/genetics.109.108480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Terenius L. Effect of anti-oestrogens on initiation of mammary cancer in the female rat. Eur J Cancer. 1971;7:65–70. https://doi.org/10.1016/0014-2964(71)90096-x.

    Article  CAS  PubMed  Google Scholar 

  214. Terenius L. Anti-oestrogens and breast cancer. Eur J Cancer. 1971;7:57–64. https://doi.org/10.1016/0014-2964(71)90095-8.

    Article  CAS  PubMed  Google Scholar 

  215. Jordan VC, Allen KE. Evaluation of the antitumour activity of the non-steroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model. Eur J Cancer. 1980;16:239–51. https://doi.org/10.1016/0014-2964(80)90156-5.

    Article  CAS  PubMed  Google Scholar 

  216. Quirke VM. Tamoxifen from failed contraceptive pill to best-selling breast cancer medicine: A case-study in pharmaceutical innovation. Front Pharmacol. 2017;8:620. https://doi.org/10.3389/fphar.2017.00620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Adjuvant Chemotherapy for Breast Cancer. JAMA. 1985;254:3461–3.

    Article  Google Scholar 

  218. Brodie AMH, Schwarzel WC, Shaikh AA, Brodie HJ. The Effect of an Aromatase Inhibitor, 4-Hydroxy-4-Androstene- 3,17-Dione, On Estrogen-Dependent Processes in Reproduction and Breast Cancer. Endocrinology. 1977;100:1684–95. https://doi.org/10.1210/endo-100-6-1684.

    Article  CAS  PubMed  Google Scholar 

  219. Kubatka P, Sadloňová V, Kajo K, Nosáľová G, Faculty J. Chemopreventive Effects of Anastrozole in a Premenopausal Breast Cancer Model. Anticancer Res. 2008;28:2819–24.

    CAS  PubMed  Google Scholar 

  220. Kubatka P, Sadlonova V, Kajo K, Machalekova K, Ostatnikova D, Nosalova G, et al. Neoplastic effects of exemestane in premenopausal breast cancer model. Neoplasma. 2008;55:538–43.

    CAS  PubMed  Google Scholar 

  221. Bhatnagar AS. The discovery and mechanism of action of letrozole. Breast Cancer Res Treat. 2007;105:7–17. https://doi.org/10.1007/s10549-007-9696-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Kubatka P, Ahlers I, Ahlersová E, Adámeková E, Luk P, Bojková B, et al. Chemoprevention of mammary carcinogenesis in female rats by rofecoxib. Cancer Lett. 2003;202:131–6. https://doi.org/10.1016/j.canlet.2003.08.006.

    Article  CAS  PubMed  Google Scholar 

  223. Okugawa H, Yamamoto D, Uemura Y, Sakaida N, Tanano A, Tanaka K, et al. Effect of perductal paclitaxel exposure on the development of MNU-induced mammary carcinoma in female S-D rats. Breast Cancer Res Treat. 2005;91:29–34. https://doi.org/10.1007/s10549-004-6455-6.

    Article  CAS  PubMed  Google Scholar 

  224. Alfaro Y, Delgado G, Cárabez A, Anguiano B, Aceves C. Iodine and doxorubicin, a good combination for mammary cancer treatment: antineoplastic adjuvancy, chemoresistance inhibition, and cardioprotection. Mol Cancer. 2013;12:45. https://doi.org/10.1186/1476-4598-12-45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Li S, Martel C, Dauvois S, Bélanger A, Labrie F. Effect of estrone on the growth of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in the rat: a model of postmenopausal breast cancer. Endocrinology. 1994;134:1352–7. https://doi.org/10.1210/endo.134.3.8119175.

    Article  CAS  PubMed  Google Scholar 

  226. Blank EW, Wong PY, Lakshmanaswamy R, Guzman R, Nandi S. Both ovarian hormones estrogen and progesterone are necessary for hormonal mammary carcinogenesis in ovariectomized ACI rats. Proc Natl Acad Sci USA. 2008;105:3527–32. https://doi.org/10.1073/pnas.0710535105.

    Article  PubMed  PubMed Central  Google Scholar 

  227. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women: The Women’s Health Initiative Randomized Trial. JAMA. 2003;289:3243–53. https://doi.org/10.1001/jama.289.24.3243.

    Article  CAS  PubMed  Google Scholar 

  228. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the women’s health initiative randomized controlled trial. J Am Med Assoc. 2002;288:321–33. https://doi.org/10.1001/jama.288.3.321.

    Article  CAS  Google Scholar 

  229. Lanari C, Wargon V, Rojas P, Molinolo AA. Antiprogestins in breast cancer treatment: Are we ready? Endocr Relat Cancer. 2012;19:R35–50. https://doi.org/10.1530/ERC-11-0378.

    Article  CAS  PubMed  Google Scholar 

  230. Líška J, Brtko J, Dubovický M, Macejová D, Kissová V, Polák Š, et al. Relationship between histology, development and tumorigenesis of mammary gland in female rat. Exp Anim. 2016;65:1–9. https://doi.org/10.1538/expanim.15-0055.

    Article  PubMed  Google Scholar 

  231. Russo J, Gusterson BA, Rogers AE, Russo IH, Wellings SR, Van Zwieten MJ. Comparative study of human and rat mammary tumorigenesis. Lab Investig. 1990;62:244–78.

    CAS  PubMed  Google Scholar 

  232. Flister MJ, Endres BT, Rudemiller N, Sarkis AB, Santarriaga S, Roy I, et al. CXM– a new tool for mapping breast cancer risk in the tumor microenvironment. Cancer Res. 2014;74:6419–29. https://doi.org/10.1158/0008-5472.can-13-3212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Flister MJ, Tsaih SW, Stoddard A, Plasterer C, Jagtap J, Parchur AK, et al. Host genetic modifiers of nonproductive angiogenesis inhibit breast cancer. Breast Cancer Res Treat. 2017;165:53–64. https://doi.org/10.1007/s10549-017-4311-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Russo J, Moral R, Balogh GA, Mailo D, Russo IH. The protective role of pregnancy in breast cancer. Breast Cancer Res. 2005;7:131–42. https://doi.org/10.1186/bcr1029.

    Article  PubMed  PubMed Central  Google Scholar 

  235. Russo IH, Koszalka M, Russo J. Human chorionic gonadotropin and rat mammary cancer prevention. J Natl Cancer Inst. 1990;82:1286–9. https://doi.org/10.1093/jnci/82.15.1286.

    Article  CAS  PubMed  Google Scholar 

  236. Russo J, Balogh GA, Heulings R, Mailo DA, Moral R, Russo PA, et al. Molecular basis of pregnancy-induced breast cancer protection. Eur J Cancer Prev. 2006;15:306–42. https://doi.org/10.1097/00008469-200608000-00006.

    Article  CAS  PubMed  Google Scholar 

  237. Dao TL, Sunderland H. Mammary Carcinogenesis by 3-Methylcholanthrene. I. Hormonal Aspects in Tumor Induction and Growth. JNCI J Natl Cancer Inst. 1959;23:567–85.

    CAS  PubMed  Google Scholar 

  238. Boettcher AN, Schachtschneider KM, Schook LB, Tuggle CK. Swine models for translational oncological research: an evolving landscape and regulatory considerations. Mamm Genome. 2022;33:230–40. https://doi.org/10.1007/s00335-021-09907-y.

    Article  PubMed  Google Scholar 

  239. Mondal P, Bailey KL, Cartwright SB, Band V, Carlson MA. Large Animal Models of Breast Cancer. Front Oncol. 2022;12. https://doi.org/10.3389/fonc.2022.788038.

  240. Lin JH. Species similarities and differences in pharmacokinetics. Drug Metab Dispos Drug Metab Dispos. 1995;23:1008–21.

    CAS  PubMed  Google Scholar 

  241. Harman RM, Das SP, Bartlett AP, Rauner G, Donahue LR, Van de Walle GR. Beyond tradition and convention: benefits of non-traditional model organisms in cancer research. Cancer Metastasis Rev. 2021;40:47–69.

    Article  PubMed  Google Scholar 

  242. Abdelmegeed SM, Mohammed S. Canine mammary tumors as a model for human disease. Oncol Lett. 2018;15:8195–205. https://doi.org/10.3892/ol.2018.8411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Wiese DA, Thaiwong T, Yuzbasiyan-Gurkan V, Kiupel M. Feline mammary basal-like adenocarcinomas: a potential model for human triple-negative breast cancer (TNBC) with basal-like subtype. BMC Cancer. 2013;13:403. https://doi.org/10.1186/1471-2407-13-403.

    Article  PubMed  PubMed Central  Google Scholar 

  244. Gray M, Meehan J, Martínez-Pérez C, Kay C, Turnbull AK, Morrison LR, et al. Naturally-Occurring Canine Mammary Tumors as a Translational Model for Human Breast Cancer. Front Oncol. 2020;10:617. https://doi.org/10.3389/fonc.2020.00617.

    Article  PubMed  PubMed Central  Google Scholar 

  245. Gordon I, Paoloni M, Mazcko C, Khanna C. The Comparative Oncology Trials Consortium: Using Spontaneously Occurring Cancers in Dogs to Inform the Cancer Drug Development Pathway. PLOS Med. 2009;6:e1000161. https://doi.org/10.1371%2Fjournal.pmed.1000161.

    Article  PubMed  PubMed Central  Google Scholar 

  246. Queiroga FL, Raposo T, Carvalho MI, Prada J, Pires I. Canine mammary tumours as a model to study human breast cancer: Most recent findings. In Vivo. 2011;25:455–65.

    PubMed  Google Scholar 

  247. Abadie J, Nguyen F, Loussouarn D, Peña L, Gama A, Rieder N, et al. Canine invasive mammary carcinomas as models of human breast cancer. Part 2: immunophenotypes and prognostic significance. Breast Cancer Res Treat. 2018;167:459–68. https://doi.org/10.1007/s10549-017-4542-8.

    Article  CAS  PubMed  Google Scholar 

  248. Du J, Zhao Q, Liu K, Li Z, Fu F, Zhang K, et al. FGFR2/STAT3 Signaling Pathway Involves in the Development of MMTV-Related Spontaneous Breast Cancer in TA2 Mice. Front Oncol. 2020;10:652. https://doi.org/10.3389/fonc.2020.00652.

    Article  PubMed  PubMed Central  Google Scholar 

  249. Lamballe F, Ahmad F, Vinik Y, Castellanet O, Daian F, Müller AK, et al. Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance. Adv Sci. 2021;8:2003049. https://doi.org/10.1002/advs.202003049.

    Article  CAS  Google Scholar 

  250. Kau P, Nagaraja GM, Zheng H, Gizachew D, Galukande M, Krishnan S, et al. A mouse model for triple-negative breast cancer tumor-initiating cells (TNBC-TICs) exhibits similar aggressive phenotype to the human disease. BMC Cancer. 2012;12:120. https://doi.org/10.1186/1471-2407-12-120.

    Article  Google Scholar 

  251. Alsaihati BA, Ho K-L, Watson J, Feng Y, Wang T, Dobbin KK, et al. Canine tumor mutational burden is correlated with TP53 mutation across tumor types and breeds. Nat Commun. 2021;12:4670. https://doi.org/10.1038/s41467-021-24836-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Machiela MJ, Chanock SJ. GWAS is going to the dogs. Genome Biol. 2014;15:105. https://doi.org/10.1186/gb4166.

    Article  PubMed  PubMed Central  Google Scholar 

  253. Melin M, Rivera P, Arendt M, Elvers I, Murén E, Gustafson U, et al. Genome-Wide Analysis Identifies Germ-Line Risk Factors Associated with Canine Mammary Tumours. PLoS Genet. 2016;12:e1006029. https://doi.org/10.1371/journal.pgen.1006029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Uva P, Aurisicchio L, Watters J, Loboda A, Kulkarni A, Castle J, et al. Comparative expression pathway analysis of human and canine mammary tumors. BMC Genomics. 2009;10:135. https://doi.org/10.1186/1471-2164-10-135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Bukowski JA, Wartenberg D, Goldschmidt M. Environmental causes for sinonasal cancers in pet dogs, and their usefulness as sentinels of indoor cancer risk. J Toxicol Environ Heal Part A. 1998;54:579–91. https://doi.org/10.1080/009841098158719.

    Article  CAS  Google Scholar 

  256. Munson L, Moresco A. Comparative pathology of mammary gland cancers in domestic and wild animals. Breast Dis. 2007;28:7–21. https://doi.org/10.3233/bd-2007-28102.

    Article  CAS  PubMed  Google Scholar 

  257. Wei WZ, Jones RF, Juhasz C, Gibson H, Veenstra J. Evolution of animal models in cancer vaccine development. Vaccine. 2015;33:7401–7. https://doi.org/10.1016%2Fj.vaccine.2015.07.075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Powell EJ, Charley S, Boettcher AN, Varley L, Brown J, Schroyen M, et al. Creating effective biocontainment facilities and maintenance protocols for raising specific pathogen-free, severe combined immunodeficient (SCID) pigs. Lab Anim. 2018;52:402–12. https://doi.org/10.1177/0023677217750691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Boettcher AN, Loving CL, Cunnick JE, Tuggle CK. Development of severe combined immunodeficient (SCID) pig models for translational cancer modeling: Future insights on how humanized SCID pigs can improve preclinical cancer research. Front Oncol Frontiers Media S A. 2018;8:559. https://doi.org/10.3389/fonc.2018.00559.

    Article  Google Scholar 

  260. Dalgaard L. Comparison of minipig, dog, monkey and human drug metabolism and disposition. J Pharmacol Toxicol Methods. 2015;74:80–92. https://doi.org/10.1016/j.vascn.2014.12.005.

    Article  CAS  PubMed  Google Scholar 

  261. Skaanild M. Porcine Cytochrome P450 and Metabolism. Curr Pharm Des. 2006;12:1421–7. https://doi.org/10.2174/138161206776361183.

    Article  CAS  PubMed  Google Scholar 

  262. Petri N, Bergman E, Forsell P, Hedeland M, Bondesson U, Knutson L, et al. First-pass effects of verapamil on the intestinal absorption and liver disposition of fexofenadine in the porcine model. Drug Metab Dispos. 2006;34:1182–9. https://doi.org/10.1124/dmd.105.008409.

    Article  CAS  PubMed  Google Scholar 

  263. Segovia-Mendoza M, Morales-Montor J. Immune tumor microenvironment in breast cancer and the participation of estrogens and its receptors into cancer physiopathology. Front Immunol. 2019;10. https://doi.org/10.3389/fimmu.2019.00348.

  264. Standish LJ, Sweet ES, Novack J, Wenner CA, Bridge C, Nelson A, et al. Breast Cancer and the Immune System. J Soc Integr Oncol. 2008;6:168.

    Google Scholar 

  265. Murray TJ, Ucci AA, Maffini MV, Sonnenschein C, Soto AM. Histological analysis of low dose NMU effects in the rat mammary gland. BMC Cancer. 2009;9:267. https://doi.org/10.1186/1471-2407-9-267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Kubatka P, Ahlersová E, Ahlers I, Bojková B, Kalická K, Adámeková E, et al. Variability of Mammary Carcinogenesis Induction in Female Sprague-Dawley and Wistar:Han Rats: the Effect of Season and Age. Physiol Res. 2002;51:633–40.

    CAS  PubMed  Google Scholar 

  267. Lindsey WF, Beattie CW, Das Gupta TK. Influence of the Estrous Cycle during Carcinogen Exposure on Nitrosomethylurea-induced Rat Mammary Carcinoma. Cancer Res. 1981;41:3857–62.

    CAS  PubMed  Google Scholar 

  268. Moore C, Bachhuber A, Gould M. Relationship of mammary tumor susceptibility, mammary cell-mediated mutagenesis, and metabolism of polycyclic aromatic hydrocarbons in four types of rats. J Natl Cancer Inst. 1983;70:777–84.

    CAS  PubMed  Google Scholar 

  269. Syndor KL, Butenandt O, Brillantes FP, Huggins C. Race-strain factor related to hydrocarbon-induced mammary cancer in rats. J Natl Cancer Inst. 1962;29:805–14.

    Google Scholar 

  270. Kacew S, Ruben Z, Mcconnell RF. Strain as a Determinant Factor in the Differential Responsiveness of Rats to Chemicals. Toxicol Pathol. 1995;23:701–14. https://doi.org/10.1177/019262339502300608.

    Article  CAS  PubMed  Google Scholar 

  271. Huggins CB, Ueda N, Wiessler M. N-nitroso-N-methylurea elicits mammary cancer in resistant and sensitive rat strains. Proc Natl Acad Sci USA. 1981;78:1185–8. https://doi.org/10.1073/pnas.78.2.1185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Rajkumar L, Arumugam A, Elsayed A, Schecter S, Kotkowski E, Castillo R, et al. Long-term hormonal promotion overcomes genetic resistance to mammary cancer. Steroids. 2011;76:31–7. https://doi.org/10.1016/j.steroids.2010.08.004.

    Article  CAS  PubMed  Google Scholar 

  273. Haag JD, Newton MA, Gould MN. Mammary carcinoma suppressor and susceptibility genes in the Wistar–Kyoto rat. Carcinogenesis. 1992;13:1933–5. https://doi.org/10.1093/carcin/13.10.1933.

    Article  CAS  PubMed  Google Scholar 

  274. Isaacs JT. A Mammary Cancer Suppressor Gene and Its Site of Action in the Rat. Cancer Res. 1991;51:1591–5.

    CAS  PubMed  Google Scholar 

  275. Shull JD, Pennington KL, Reindl TM, Snyder MC, Strecker TE, Spady TJ, et al. Susceptibility to estrogen-induced mammary cancer segregates as an incompletely dominant phenotype in reciprocal crosses between the ACI and copenhagen rat strains. Endocrinology. 2001;142:5124–30. https://doi.org/10.1210/endo.142.12.8530.

    Article  CAS  PubMed  Google Scholar 

  276. Vogel HH, Turner JE. Genetic component in rat mammary carcinogenesis. Radiat Res. 1982;89:264–73. https://doi.org/10.2307/3575772.

    Article  PubMed  Google Scholar 

  277. Stieber D, Piessevaux G, Rivière M, Laes J-F, Quan X, Szpirer J, et al. Isolation of two regions on rat chromosomes 5 and 18 affecting mammary cancer susceptibility. Int J Cancer. 2007;120:1678–83. https://doi.org/10.1002/ijc.22400.

    Article  CAS  PubMed  Google Scholar 

  278. Kurz SG, Hansen KK, McLaughlin MT, Shivaswamy V, Schaffer BS, Gould KA, et al. Tissue-specific actions of the Ept1, Ept2, Ept6, and Ept9 genetic determinants of responsiveness to estrogens in the female rat. Endocrinology. 2008;149:3850–9. https://doi.org/10.1210/en.2008-0173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, 14853, Ithaca, NY, USA

    James L. Miller, Arianna P. Bartlett, Rebecca M. Harman & Gerlinde R. Van de Walle

  2. Department of Veterinary & Animal Sciences, University of Massachusetts, 01003, Amherst, MA, USA

    Prabin Dhangada Majhi & D. Joseph Jerry

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  1. James L. Miller
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  2. Arianna P. Bartlett
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  3. Rebecca M. Harman
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  4. Prabin Dhangada Majhi
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  5. D. Joseph Jerry
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  6. Gerlinde R. Van de Walle
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JLM drafted the majority of the manuscript; APB was involved in manuscript writing; BH intellectually contributed to manuscript content; PKDM was involved in figure creation; DJJ and GVdW were involved in review design, providing intellectual input, and manuscript writing and editing.

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Correspondence to Gerlinde R. Van de Walle.

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Dr. D. Joseph Jerry is a member of the Editorial board of the Journal of Mammary Gland Biology and Neoplasia. All other authors have no conflicts of interest/competing interests to declare.

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Miller, J.L., Bartlett, A.P., Harman, R.M. et al. Induced mammary cancer in rat models: pathogenesis, genetics, and relevance to female breast cancer. J Mammary Gland Biol Neoplasia 27, 185–210 (2022). https://doi.org/10.1007/s10911-022-09522-w

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  • DOI: https://doi.org/10.1007/s10911-022-09522-w

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