Abstract
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.
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Aiyer HS, Gupta RC (2010) Berries and ellagic acid prevent estrogen-induced mammary tumorigenesis by modulating enzymes of estrogen metabolism. Cancer Prev Res (Phila) 3:727–737. https://doi.org/10.1158/1940-6207.CAPR-09-0260
Böttner M, Suter-Crazzolara C, Schober A, Unsicker K (1999) Expression of a novel member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage-inhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues. Cell Tissue Res 297:103–110
Bouchard D, Morisset D, Bourbonnais Y, Tremblay GM (2006) Proteins with whey-acidic-protein motifs and cancer. Lancet Oncol 7:167–174. https://doi.org/10.1016/S1470-2045(06)70579-4
Bulun SE, Chen D, Moy I, Brooks DC, Zhao H (2012) Aromatase, breast cancer and obesity: a complex interaction. Trends Endocrinol Metab 23:83–89. https://doi.org/10.1016/j.tem.2011.10.003
Candido J, Hagemann T (2013) Cancer-related inflammation. J Clin Immunol 33(Suppl 1):S79–S84. https://doi.org/10.1007/s10875-012-9847-0
Cavalieri E, Frenkel K, Liehr JG, Rogan E, Roy D (2000) Estrogens as endogenous genotoxic agents–DNA adducts and mutations. J Natl Cancer Inst Monogr 27:75–93
Coleman KD, Wright JA, Ghosh M, Wira CR, Fahey JV (2009) Estradiol modulation of hepatocyte growth factor by stromal fibroblasts in the female reproductive tract. Fertil Steril 92:1107–1109. https://doi.org/10.1016/j.fertnstert.2008.10.047
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
Degen GH, Janning P, Diel P, Bolt HM (2002) Estrogenic isoflavones in rodent diets. Toxicol Lett 128:145–157
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
Dinkova-Kostova AT, Talalay P (2010) NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys 501:116–123. https://doi.org/10.1016/j.abb.2010.03.019
Eeckhoute J, Keeton EK, Lupien M, Krum SA, Carroll JS, Brown M (2007) Positive cross-regulatory loop ties GATA-3 to estrogen receptor alpha expression in breast cancer. Cancer Res 67:6477–6483. https://doi.org/10.1158/0008-5472.CAN-07-0746
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
Haq F, Mahoney M, Koropatnick J (2003) Signaling events for metallothionein induction. Mutat Res 533:211–226
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
Helle J, Bader MI, Keiler AM et al (2016) Cross-talk in the female rat mammary gland: influence of aryl hydrocarbon receptor on estrogen receptor signaling. Environ Health Perspect 124:601–610. https://doi.org/10.1289/ehp.1509680
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
Lanigan F, O’Connor D, Martin F, Gallagher WM (2007) Molecular links between mammary gland development and breast cancer. Cell Mol Life Sci 64:3159–3184. https://doi.org/10.1007/s00018-007-7386-2
Lehmann L, Jiang L, Wagner J (2008) Soy isoflavones decrease the catechol-O-methyltransferase-mediated inactivation of 4-hydroxyestradiol in cultured MCF-7 cells. Carcinogenesis 29:363–370. https://doi.org/10.1093/carcin/bgm235
Li SA, Weroha SJ, Tawfik O, Li JJ (2002) Prevention of solely estrogen-induced mammary tumors in female ACI rats by tamoxifen: evidence for estrogen receptor mediation. J Endocrinol 175:297–305
Li KM, Todorovic R, Devanesan P et al (2004) Metabolism and DNA binding studies of 4-hydroxyestradiol and estradiol-3,4-quinone in vitro and in female ACI rat mammary gland in vivo. Carcinogenesis 25:289–297. https://doi.org/10.1093/carcin/bgg191
Lu SC (2013) Glutathione synthesis. Biochim Biophys Acta 1830:3143–3153. https://doi.org/10.1016/j.bbagen.2012.09.008
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
Massague J (2012) TGFbeta signalling in context. Nat Rev Mol Cell Biol 13:616–630. https://doi.org/10.1038/nrm3434
Meier-Abt F, Bentires-Alj M (2014) How pregnancy at early age protects against breast cancer. Trends Mol Med 20:143–153. https://doi.org/10.1016/j.molmed.2013.11.002
Mense SM, Singh B, Remotti F, Liu X, Bhat HK (2009) Vitamin C and alpha-naphthoflavone prevent estrogen-induced mammary tumors and decrease oxidative stress in female ACI rats. Carcinogenesis 30:1202–1208. https://doi.org/10.1093/carcin/bgp093
Mesia-Vela S, Sanchez R, Reuhl KR, Conney AH, Kauffman FC (2005) Metabolism of 17β-estradiol in ACI rat liver and mammary gland after chronic estradiol treatment. In: Li J, Li S, Llombart-Bosch A (eds) Hormonal carcinogenesis IV, 1st edn. Springer, US, pp 367–374
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
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 24:697–702
Rosner W, Hankinson SE, Sluss PM, Vesper HW, Wierman ME (2013) Challenges to the measurement of estradiol: an endocrine society position statement. J Clin Endocrinol Metab 98:1376–1387. https://doi.org/10.1210/jc.2012-3780
Ruttkay-Nedecky B, Nejdl L, Gumulec J et al (2013) The role of metallothionein in oxidative stress. Int J Mol Sci 14:6044–6066. https://doi.org/10.3390/ijms14036044
Safe S, Kim K (2008) Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways. J Mol Endocrinol 41:263–275. https://doi.org/10.1677/JME-08-0103
Samavat H, Kurzer MS (2015) Estrogen metabolism and breast cancer. Cancer Lett 356:231–243. https://doi.org/10.1016/j.canlet.2014.04.018
Shull JD, Spady TJ, Snyder MC, Johansson SL, Pennington KL (1997) Ovary-intact, but not ovariectomized female ACI rats treated with 17beta-estradiol rapidly develop mammary carcinoma. Carcinogenesis 18:1595–1601
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
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
Sobecki M, Mrouj K, Colinge J et al (2017) Cell-cycle regulation accounts for variability in Ki-67 expression levels. Cancer Res 77:2722–2734. https://doi.org/10.1158/0008-5472.CAN-16-0707
Stanczyk FZ, Mathews BW, Sherman ME (2015) Relationships of sex steroid hormone levels in benign and cancerous breast tissue and blood: a critical appraisal of current science. Steroids 99:91–102. https://doi.org/10.1016/j.steroids.2014.12.011
Taioli E, Im A, Xu X, Veenstra TD, Ahrendt G, Garte S (2010) Comparison of estrogens and estrogen metabolites in human breast tissue and urine. Reprod Biol Endocrinol 8:93. https://doi.org/10.1186/1477-7827-8-93
Takahashi S (2015) Positive and negative regulators of the metallothionein gene (review). Mol Med Rep 12:795–799. https://doi.org/10.3892/mmr.2015.3459
Thomas C, Gustafsson JA (2015) Progesterone receptor-estrogen receptor crosstalk: a novel insight. Trends Endocrinol Metab 26:453–454. https://doi.org/10.1016/j.tem.2015.08.002
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
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
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
Weroha SJ, Li SA, Tawfik O, Li JJ (2006) Overexpression of cyclins D1 and D3 during estrogen-induced breast oncogenesis in female ACI rats. Carcinogenesis 27:491–498. https://doi.org/10.1093/carcin/bgi278
Yager JD (2015) Mechanisms of estrogen carcinogenesis: the role of E2/E1-quinone metabolites suggests new approaches to preventive intervention—a review. Steroids 99:56–60. https://doi.org/10.1016/j.steroids.2014.08.006
Yeager RL, Reisman SA, Aleksunes LM, Klaassen CD (2009) Introducing the “TCDD-inducible AhR-Nrf2 gene battery“. Toxicol Sci 111:238–246. https://doi.org/10.1093/toxsci/kfp115
Zordoky BN, El-Kadi AO (2009) Role of NF-kappaB in the regulation of cytochrome P450 enzymes. Curr Drug Metab 10:164–178
Acknowledgements
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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Pemp, D., Esch, H.L., Hauptstein, R. et al. Novel insight in estrogen homeostasis and bioactivity in the ACI rat model of estrogen-induced mammary gland carcinogenesis. Arch Toxicol 93, 1979–1992 (2019). https://doi.org/10.1007/s00204-019-02483-w
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DOI: https://doi.org/10.1007/s00204-019-02483-w