Inhibition of Mammary Tumorigenesis by Estrogen and Progesterone in Genetically Engineered Mice

  • D. Medina
  • F. S. Kittrell
  • A. Tsimelzon
  • S. A. W. Fuqua
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2007/1)


Estrogen and progesterone play a critical role in normal and neoplastic development of the mammary gland. A long duration of estrogen and progesterone exposure is associated with increased breast cancer risk, and a short duration of the same doses of these hormones is associated with a reduced breast cancer risk. The protective effects of estrogen and progesterone have been extensively studied in animal models. Several studies have demonstrated that these hormones induce persistent and long-lasting alterations in gene expression in the mammary epithelial cells. In the experiments discussed herein, the protective effect of estrogen and progesterone is shown to occur in genetically engineered mice (the p53-null mammary gland). The protective effect is associated with a decrease in cell proliferation. The effects of hormones seem to manifest as a delay in premalignant progression. In the nontumor-bearing glands of hormone-treated mice, premalignant foci are present at the time the control glands are actively developing mammary tumors. If the hormone-treated cells are transplanted from the treated host to the untreated host, the cells resume their predetermined tumorigenic potential. The protective effect reflects both host-mediated factors (either stroma-determined or systemic factors) and mammary epithelial intrinsic changes. If normal, untreated p53 cells are transplanted into a host that has been previously treated with a short dose of hormones, the cells exhibit a significant delay in tumorigenesis. The relative contributions of host-mediated factors and mammary cell intrinsic factors remain to be determined. Current studies are moving this research area from the biological to the molecular realm and from the rodent models to human studies and offer the potential for directing prevention efforts at specific molecular targets.


Breast Cancer Mammary Epithelial Cell Tumorigenic Potential Mammary Tumorigenesis Engineer Mouse Model 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The original results discussed here were supported by NCI P01 CA064255. We greatly appreciate the technical assistance of Frances Kittrell, Anne Shepard, David Edwards, and Irma Parra, and the secretarial skills of Kathy Key.


  1. Abrams TJ, Guzman RC, Swanson SM, Thordarson G, Talamantes F, Nandi S (1998) Changes in the parous rat mammary gland environment are involved in parity-associated protection against mammary carcinogenesis. Anticancer Res 18:4115–4121PubMedGoogle Scholar
  2. Ahlgren M, Melbye M, Wohlfahrt J, Sorensen TL (2004) Growth patterns and the risk of breast cancer in women. N Engl J Med 351:1619–1626PubMedCrossRefGoogle Scholar
  3. American Cancer Society (2006) Cancer facts and figures 2006. Accessed 10 Aug 2007Google Scholar
  4. Barcellos-Hoff MH, Ravani SA (2000) Irradiated mammary gland stroma promotes the expression of tumorigenic potential by unirradiated epithelial cells. Cancer Res 60:1254–1260PubMedGoogle Scholar
  5. Beatson GT (1896) On the treatment of inoperable cases of carcinoma of the mamma. Suggestions for a new method of treatment with illustrative cases. Lancet 2:104–107CrossRefGoogle Scholar
  6. Blakely CM, Stoddard AJ, Belka GK, Dugan KD, Notarfrancesco KL, Moody SE, D'Cruz CM, Chodosh LA (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 66:6421–6431PubMedCrossRefGoogle Scholar
  7. Blakely CM, Stoddard AJ, Belka GK, Dugan KD, Notarfrancesco KL, Moody SE, D'Cruz CM, Chodosh LA (2007) Correction: pregnancy-induced protection against mammary tumorigenesis. Cancer Res 67:844–845Google Scholar
  8. Brodie A, Lu Q, Liu Y, Long B (1999) Aromatase inhibitors and their antitumor effects in model systems. Endocr Relat Cancer 6:205–210PubMedCrossRefGoogle Scholar
  9. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA 289:3243–3253PubMedCrossRefGoogle Scholar
  10. D'Cruz CM, Moody SE, Master SR, Hartman JL, Keiper EA, Imielinski MB, Cox JD, Wang JY, Ha SI, Keister BA, Chodosh LA (2002) Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland. Mol Endocrinol 16:2034–2051PubMedCrossRefGoogle Scholar
  11. Goss PE (2004) Changing clinical practice: extending the benefits of adjuvant endocrine therapy in breast cancer. Semin Oncol 31:15–22PubMedCrossRefGoogle Scholar
  12. Henderson BE, Ross RK, Pike MC (1991) Toward the primary prevention of cancer. Science 254:1131–1138PubMedCrossRefGoogle Scholar
  13. Jordan VC, Labadidi MK, Langan-Fahey S (1991) Suppression of mouse mammary tumorigenesis by long-term tamoxifen therapy. J Natl Cancer Inst 83:492–496PubMedCrossRefGoogle Scholar
  14. Maffini MV, Soto AM, Calabro JM, Ucci AA, Sonnenschein C (2004) The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci 117:1495–1502PubMedCrossRefGoogle Scholar
  15. Medina D (2005) Mammary developmental fate and breast cancer risk. Endocr Relat Cancer 21:1–13Google Scholar
  16. Medina D, Kittrell FS, Shepard A, Stephens LC, Jiang C, Lu J, Allred DC, McCarthy M, Ullrich RL (2002) Biological and genetic properties of the p53 null preneoplastic mammary epithelium. FASEB J 16:881–883PubMedGoogle Scholar
  17. Nandi S, Guzman RC, Thordarson G, Rajkumar L (2005) Estrogen can prevent breast cancer by mimicking the protective effect of pregnancy. In: Li JJ, Li SA, Llombart-Bosch A (eds) Hormonal carcinogenesis IV. Springer, Berlin Heidelberg New York, pp 153–165Google Scholar
  18. Osborne CK (1998) Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609–1618PubMedCrossRefGoogle Scholar
  19. Rajkumar L, Kittrell FS, Guzman RC, Brown PH, Nandi S, Medina D (2007) Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models. Breast Cancer Res 9:R12PubMedCrossRefGoogle Scholar
  20. Reddy M, Nguyen S, Farjamrad F, Laxminarayan S, Lakshmanaswamy R, Guzman R, Yang J, Nandi S (2002) Short-term hormone treatment with pregnancy levels of estradiol prevents mammary carcinogenesis by preventing promotion of carcinogen initiated cells. Proceedings of the American Association for Cancer Research Annual Meeting. American Association for Cancer Research 43:1964Google Scholar
  21. Santen RJ (2003) Risk of breast cancer with progestins: critical assessment of current data. Steroids 68:953–964PubMedCrossRefGoogle Scholar
  22. Schedin P, Mitrenga T, McDaniel S, Kaeck KM (2004) Mammary ECM composition and function are altered by reproductive state. Mol Carcinogen 41:207–220CrossRefGoogle Scholar
  23. Sivaraman L, Stephens LC, Markaverich BM, Clark JA, Krnacik S, Conneely OM, O'Malley BW, Medina D (1998) Hormone-induced refractoriness to mammary carcinogenesis in Wistar-Furth rats. Carcinogenesis 19:1573–1581PubMedCrossRefGoogle Scholar
  24. Sivaraman L, Conneely OM, Medina D, O'Malley BW (2001) p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis. Proc Natl Acad Sci U S A 98:12379–12384PubMedCrossRefGoogle Scholar
  25. Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, Lane DS, Hubbell FA, Assaf AR, Sarto GE, Schenken RS, Yasmeen S, et al (2006) Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 295:1647–1657PubMedCrossRefGoogle Scholar
  26. Swanson SM, Guzman RC, Collins G, Tafoya P, Thordarson G, Talamantes F, Nandi S (1995) Refractoriness to mammary carcinogenesis in the parous mouse is reversible by hormonal stimulation induced by pituitary isografts. Cancer Lett 90:171–181PubMedCrossRefGoogle Scholar
  27. Thordarson G, Jin E, Guzman RC, Swanson SM, Nandi S, Talamantes F (1995) Refractoriness to mammary tumorigenesis in parous rats: is it caused by persistent changes in the hormonal environment or permanent biochemical alterations in the mammary epithelia? Carcinogenesis 16:2847–2853PubMedCrossRefGoogle Scholar
  28. Thordarson G, Van Horn K, Guzman RC, Nandi S, Talamantes F (2001) Parous rats regain high susceptibility to chemically induced mammary cancer after treatment with various mammotropic hormones. Carcinogenesis 22:1027–1033PubMedCrossRefGoogle Scholar
  29. Thordarson G, Semaan S, Low C, Ochoa D, Leong H, Rajkumar L, Guzman RC, Nandi S, Talamantes F (2004a) Mammary tumorigenesis in growth hormone deficient spontaneous dwarf rats; effects of hormonal treatments. Breast Cancer Res Treat 87:277–290PubMedCrossRefGoogle Scholar
  30. Thordarson G, Slusher N, Leong H, Ochoa D, Rajkumar L, Guzman R, Nandi S, Talamantes F (2004b) Insulin-like growth factor (IGF)-I obliterates the pregnancy-associated protection against mammary carcinogenesis in rats: evidence that IGF-I enhances cancer progression through estrogen receptor-alpha activation via the mitogen-activated protein kinase pathway. Breast Cancer Res 6:R423–R436PubMedCrossRefGoogle Scholar
  31. Yang J, Yoshizawa K, Nandi S, Tsubura A (1999) Protective effects of pregnancy and lactation against N-methyl-N-nitrosourea-induced mammary carcinomas in female Lewis rats. Carcinogenesis 20:623–628PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • D. Medina
    • 1
  • F. S. Kittrell
    • 1
  • A. Tsimelzon
    • 1
  • S. A. W. Fuqua
    • 1
  1. 1.Department of Molecular and Cellular Biology, and Baylor Breast CenterBaylor College of MedicineHoustonUSA

Personalised recommendations