Novel insight in estrogen homeostasis and bioactivity in the ACI rat model of estrogen-induced mammary gland carcinogenesis
Novel insight in estrogen homeostasis and bioactivity in the ACI rat model of estrogen-induced mammary gland carcinogenesis
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对雌激素诱导乳腺癌的 ACI 大鼠模型中雌激素稳态和生物活性的新见解
作者：
Daniela Pemp;Harald L. Esch;R. Hauptstein;F. Möller;O. Zierau;M. Bosland;Leo N. Geppert;Carolin Kleider;Katharina Schlereth;G. Vollmer;L. Lehmann
尽管广泛用于研究17β-雌二醇（E2）诱导的乳腺（MG）致癌作用及其预防，但雌激素稳态及其在雌性August Copenhagen Irish（ACI）大鼠模型中的意义尚不清楚。因此，使用两种不同的饮食，在38个血浆和52个组织中通过质谱测定了12种雌激素（包括代谢物和缀合物）的水平，这些血浆和组织表现出从正常到可触及肿瘤的表型，这些表型来自代表性ACI研究。在组织中，40个转录本编码的蛋白质参与雌激素（biotrans）的形成，ESR 1介导的信号，增殖和氧化应激进行了分析（TaqMan PCR）。通过双向方差分析分析组织（病理）表型和饮食对雌激素和转录水平的影响，并通过多元线性回归模型确定影响组织中雌激素水平和生物活性的解释变量。组织和血浆中的雌激素谱以及Hsd 17 b1水平对组织内E2和E1水平的影响最终表明，ACI肿瘤中通过Hsd 17 B1介导的E1转化在乳房内形成E2。ACI肿瘤的增殖受Egfr、Igf 1 r、Hgf和Met水平的影响。2-MeO-E1是检测到的唯一高于28-42 fmol/g的氧化雌激素代谢物，主要在增生组织中观察到，E1的组织内转化似乎有助于其水平。在增生和肿瘤组织中观察到的2-MeO-E1的发生与更高水平的氧化应激的关联仍然不明确。因此，本研究为ACI模型中观察到的先前和未来结果提供了机制解释。
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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影响因子：
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作者：
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通讯作者：
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作者：
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作者：
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作者：
Rosner, William;Hankinson, Susan E.;Wierman, Margaret E.
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