Inhibition of Mammary Tumorigenesis by Estrogen and Progesterone in Genetically Engineered Mice
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.
KeywordsBreast Cancer Mammary Epithelial Cell Tumorigenic Potential Mammary Tumorigenesis Engineer Mouse Model
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.
- American Cancer Society (2006) Cancer facts and figures 2006. http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf. Accessed 10 Aug 2007Google Scholar
- 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
- 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
- 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
- Medina D (2005) Mammary developmental fate and breast cancer risk. Endocr Relat Cancer 21:1–13Google Scholar
- 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
- 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
- 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
- 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
- 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