Influence of tissue-specific isoflavone profiles on generation, activation and action of 17â-estradiol in the human and rat mammary gland
Zusammenfassung der Projektergebnisse
Despite the importance of the female sex hormone 17β-estradiol in the etiology of breast cancer (by constituting a precursor of estrogen quinones able to react with DNA forming DNA adducts and by controlling proliferation via estrogen receptors), there were no studies available analyzing levels of estrogens in a) characterized breast tissues of women without breast cancer using b) specific methods for quantitation allowing differentiation between free estrogens and conjugates. Likewise, estrogen (biotrans)formation during 17β-estradiol-induced carcinogenesis of the breast in the ACI rat model had not been investigated. As a consequence, the impact of isoflavones, which are widely discussed to affect breast cancer risk, thereon was unclear. Thus, prior to analyzing the effect of isoflavones, the aim was (i) to identify variables other than isoflavones which affect estrogen levels in human breast tissue and (ii) describe estrogen profiles during 17β-estradiol-induced carcinogenesis in ACI rats. The impact of isoflavones was investigated by analysis of mammoplasty specimen derived from women either consuming an isoflavone-rich extract for 1 week or consuming their normal soy-rich or Western diet. In the animal experiments, female ACI rats were exposed either to isoflavone-depleted or isoflavone-rich diet starting with conception. Furthermore, a subgroup on isoflavone-depleted diet was fed isoflavonerich diet for 1 week (diet swap) prior to analysis of breast tissues and plasmas. In the cancer experiment, carcinogenesis of the breast was induced by silastic implant containing 17β-estradiol. A comprehensive quantitative description of 17β-estradiol, estrone and their conjugates and metabolites (total 17 estrogens) as well as of 27 transcripts involved in their (biotrans)formation, and regulation thereof in human breast adipose and glandular tissues derived from wellcharacterized human mammoplasty specimen and breast tissues of rats was achieved. Multivariate linear regression models using stepwise forward selection revealed that some but not all variables affecting levels of estrogens differed between breast glandular and adipose tissues. In general, levels of estrogens were determined by both extra-tissue (e.g. Body-Mass-Index, menopause) and intra-tissue (e.g. CYP19A1 in breast adipose tissue) (biotrans)formation but also by tissue characteristics such as percentage of oil. Although levels of the isoflavone genistein in glandular tissues (but not intervention with isoflavone-rich extract) were significantly positively associated with levels of 17β-estradiol in glandular tissues, no effect of genistein on fluxes of estrogen-DNA-adducts determined by computational network modeling and even negative association with activation of estrogen receptors was observed. Isoflavone profiles in plasma were comparable to those in breast tissue whereas estrogen profiles differed between plasma and breast tissue. Surprisingly, despite most levels of and ratios between estrogens and even qualitative occurrences of estrogen conjugates differed significantly between ACI rats and humans, in the diet swap experiment, lifelong isoflavone-rich diet affected 17β-estradiol levels and estrogen receptor activation in breast tissue similar to intra-tissue levels of genistein in human glandular tissues. Also, the cancer experiment tended to support impact of isoflavone-rich diet on levels of 17β-estradiol in the group with placebo implant (which is comparable to the diet swap experiment, but at older age of the animals). However, instead of a decrease in proliferation, an increase in differentiation was induced by isoflavone-rich diet. Moreover, in the ACI cancer experiment, hyperplastic tissues were characterized by maximum formation and oxidative metabolism of estrone and cellular (oxidative) stress whereas palpable tumors exhibited highest levels of 17βestradiol and estrogen receptor activation. Lifelong isoflavone-rich diet increased differentiation and decreased proliferation in normal and hyperplastic tissues but increased 17β-estradiol/estrone ratio in palpable tumors. Taken together, intra-tissue levels of genistein seem to increase tissue levels of E2 without exhibiting adverse effect on genotoxic stress and even inducing putatively beneficial effect on estrogen-receptor activation. Cross-species comparability between human and ACI rat model was better than anticipated.
Projektbezogene Publikationen (Auswahl)
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(2014) Isoflavone und ihre Wirkung: Datenlage und aktuelle Forschungsprojekte [dt]. Lebensmittelchemie 68, 1-16
Kulling SE, and Lehmann L
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(2015). Analyse von Estrogen-Konjugaten - Einflüsse von isoflavonhaltigen Sojaprodukten [dt]. chrom+food FORUM 09/2015
Kleider C, and Lehmann L
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(2015). Dose-dependent effects of isoflavone exposure during early lifetime on the rat mammary gland: Studies on estrogen sensitivity, isoflavone metabolism, and DNA methylation. Mol Nutr Food Res. 59(2): 270-283
Blei T, Soukup ST, Schmalbach K, Pudenz M, Möller FJ, Egert B, Wörtz N, Kurrat A, Müller D, Vollmer G, Gerhäuser C, Lehmann L, Kulling SE, Diel P
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(2016). Isoflavones: Toxicological aspects and efficacy. In: Nutraceuticals: Efficacy, Safety and Toxicity edited by R.C. Gupta. Elsevier, pp. 467-489
Esch HL, Kleider C, Scheffler A, Lehmann L
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(2016). Soy isoflavone exposure through all life stages accelerates 17βestradiol-induced mammary tumor onset and growth, yet reduces tumor burden, in ACI rats. Arch Toxicol. 90(8):1907-1916
Möller FJ, Pemp D, Soukup ST, Wende K, Zhang X, Zierau O, Muders MH, Bosland MC, Kulling SE, Lehmann L, Vollmer G
