Novel insight in estrogen homeostasis and bioactivity in the ACI rat model of estrogen-induced mammary gland carcinogenesis
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Despite being widely used to investigate 17β-estradiol (E2)-induced mammary gland (MG) carcinogenesis and prevention thereof, estrogen homeostasis and its significance in the female August Copenhagen Irish (ACI) rat model is unknown. Thus, levels of 12 estrogens including metabolites and conjugates were determined mass spectrometrically in 38 plasmas and 52 tissues exhibiting phenotypes ranging from normal to palpable tumor derived from a representative ACI study using two different diets. In tissues, 40 transcripts encoding proteins involved in estrogen (biotrans)formation, ESR1-mediated signaling, proliferation and oxidative stress were analyzed (TaqMan PCR). Influence of histo(patho)logic phenotypes and diet on estrogen and transcript levels was analyzed by 2-way ANOVA and explanatory variables influencing levels and bioactivity of estrogens in tissues were identified by multiple linear regression models. Estrogen profiles in tissue and plasma and the influence of Hsd17b1 levels on intra-tissue levels of E2 and E1 conclusively indicated intra-mammary formation of E2 in ACI tumors by HSD17B1-mediated conversion of E1. Proliferation in ACI tumors was influenced by Egfr, Igf1r, Hgf and Met levels. 2-MeO-E1, the only oxidative estrogen metabolite detected above 28–42 fmol/g, was predominately observed in hyperplastic tissues and intra-tissue conversion of E1 seemed to contribute to its levels. The association of the occurrence of 2-MeO-E1 with higher levels of oxidative stress observed in hyperplastic and tumor tissues remained equivocal. Thus, the present study provides mechanistic explanation for previous and future results observed in the ACI model.
KeywordsACI rat Mammary estrogen profile Estrogen activity Tumorigenesis Multiple linear regression
This work is part of the joint research project, IsoCross, entitled “Isoflavones: Cross-species comparison of metabolism, estrogen sensitivity, epigenetics and carcinogenesis”, which was supported in whole by grants from the German Research Foundation to L. Lehmann (DFG LE 1329/10–1) and G. Vollmer (DFG VO410/12-1).
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Conflict of interest
The authors declare that they have no conflict of interest.
- Das Gupta S, So JY, Wall B, Wahler J, Smolarek AK, Sae-Tan S, Soewono KY, Yu H, Lee MJ, Thomas PE, Yang CS, Suh N (2015) Tocopherols inhibit oxidative and nitrosative stress in estrogen-induced early mammary hyperplasia in ACI rats. Mol Carcinog 54:916–925. https://doi.org/10.1002/mc.22164 CrossRefPubMedGoogle Scholar
- Ding L, Zhao Y, Warren CL, Sullivan R, Eliceiri KW, Shull JD (2013) Association of cellular and molecular responses in the rat mammary gland to 17beta-estradiol with susceptibility to mammary cancer. BMC Cancer 13:573. https://doi.org/10.1186/1471-2407-13-573 CrossRefPubMedPubMedCentralGoogle Scholar
- Envigo (2016) Rodent diet and ingredient comparison. Technical resource. http://www.envigo.com/resources/brochures/rodent-diet-and-ingredient-comparison.pdf. Accessed 26 Feb 2019
- Fleming JM, Miller TC, Quinones M, Xiao Z, Xu X, Meyer MJ, Ginsburg E, Veenstra TD, Vonderhaar BK (2010) The normal breast microenvironment of premenopausal women differentially influences the behavior of breast cancer cells in vitro and in vivo. BMC Med 8:27. https://doi.org/10.1186/1741-7015-8-27 CrossRefPubMedPubMedCentralGoogle Scholar
- Harvell DM, Strecker TE, Tochacek M, Xie B, Pennington KL, McComb RD, Roy SK, Shull JD (2000) Rat strain-specific actions of 17beta-estradiol in the mammary gland: correlation between estrogen-induced lobuloalveolar hyperplasia and susceptibility to estrogen-induced mammary cancers. Proc Natl Acad Sci USA 97:2779–2784. https://doi.org/10.1073/pnas.050569097 CrossRefPubMedGoogle Scholar
- Kloosterboer HJ, Lofgren L, von Schoulz E, von Schoultz B, Verheul HA (2007) Estrogen and tibolone metabolite levels in blood and breast tissue of postmenopausal women recently diagnosed with early-stage breast cancer and treated with tibolone or placebo for 14 days. Reprod Sci 14:151–159. https://doi.org/10.1177/1933719106298679 CrossRefPubMedGoogle Scholar
- Luzhna L, Kutanzi K, Kovalchuk O (2015) 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 779:39–56. https://doi.org/10.1016/j.mrgentox.2014.07.006 CrossRefPubMedGoogle Scholar
- Möller FJ, Pemp D, Soukup ST, Wende K, Zhang X, Zierau O, Muders MH, Bosland MC, Kulling SE, Lehmann L, Vollmer G (2016) Soy isoflavone exposure through all life stages accelerates 17beta-estradiol-induced mammary tumor onset and growth, yet reduces tumor burden, in ACI rats. Arch Toxicol 90:1907–1916. https://doi.org/10.1007/s00204-016-1674-2 CrossRefPubMedGoogle Scholar
- Rogan EG, Badawi AF, Devanesan PD, Meza JL, Edney JA, West WW, Higginbotham SM, Cavalieri EL (2003) Relative imbalances in estrogen metabolism and conjugation in breast tissue of women with carcinoma: potential biomarkers of susceptibility to cancer. Carcinogenesis 24:697–702CrossRefPubMedGoogle Scholar
- Shull JD, Dennison KL, Chack AC, Trentham-Dietz A (2018) Rat models of 17beta-estradiol-induced mammary cancer reveal novel insights into breast cancer etiology and prevention. Physiol Genomics 50:215–234. https://doi.org/10.1152/physiolgenomics.00105.2017 CrossRefPubMedPubMedCentralGoogle Scholar
- Singh B, Bhat NK, Bhat HK (2012) Induction of NAD(P)H-quinone oxidoreductase 1 by antioxidants in female ACI rats is associated with decrease in oxidative DNA damage and inhibition of estrogen-induced breast cancer. Carcinogenesis 33:156–163. https://doi.org/10.1093/carcin/bgr237 CrossRefPubMedGoogle Scholar
- Triplett AA, Sakamoto K, Matulka LA, Shen L, Smith GH, Wagner KU (2005) Expression of the whey acidic protein (Wap) is necessary for adequate nourishment of the offspring but not functional differentiation of mammary epithelial cells. Genesis 43:1–11. https://doi.org/10.1002/gene.20149 CrossRefPubMedGoogle Scholar
- Turan VK, Sanchez RI, Li JJ, Li SA, Reuhl KR, Thomas PE, Conney AH, Gallo MA, Kauffman FC, Mesia-Vela S (2004) The effects of steroidal estrogens in ACI rat mammary carcinogenesis: 17beta-estradiol, 2-hydroxyestradiol, 4-hydroxyestradiol, 16alpha-hydroxyestradiol, and 4-hydroxyestrone. J Endocrinol 183:91–99. https://doi.org/10.1677/joe.1.05802 CrossRefPubMedGoogle Scholar
- Wang S, Dunlap TL, Huang L, Liu Y, Simmler C, Lantvit DD, Crosby J, Howell CE, Dong H, Chen SN, Pauli GF, van Breemen RB, Dietz BM, Bolton JL (2018) Evidence for chemopreventive and resilience activity of licorice: Glycyrrhiza glabra and G. inflata extracts modulate estrogen metabolism in ACI rats. Cancer Prev Res. 11:819–830. https://doi.org/10.1158/1940-6207.CAPR-18-0178 CrossRefGoogle Scholar