Cross-Talk in the Female Rat Mammary Gland: Influence of Aryl Hydrocarbon Receptor on Estrogen Receptor Signaling
Cross-Talk in the Female Rat Mammary Gland: Influence of Aryl Hydrocarbon Receptor on Estrogen Receptor Signaling
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DOI：
10.1289/ehp.1509680
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发表时间：
2016-05-01
影响因子：
10.4
通讯作者：
Kretzschmar, Georg
中科院分区：
文献类型：
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作者：
Helle, Janina;Bader, Manuela I.;Kretzschmar, Georg
背景：芳烃受体（AHR）和雌激素受体（ER）之间的串扰在女性生殖器官的信号传导过程中起着重要作用。目的：研究AHR配体3-甲基胆蒽（3-MC）对去卵巢（ovx）大鼠乳腺组织er介导的信号传导的影响。方法：激素下降14天后，ovx大鼠分别给予4 μ g/kg 17 -雌二醇（E2）、15 mg/kg 8-烯基柚皮素（8-PN）、15 mg/kg 3- mc或这些化合物（E2 + 3- mc、8-PN + 3- mc）的组合治疗3天。采用乳腺全载标本计数乳腺终末芽（TEBs）。通过蛋白质表达研究（免疫组织化学、免疫荧光）、cDNA微阵列、途径分析和定量实时聚合酶链反应（qPCR）来评估AHR-和er介导的信号通路之间的相互作用。结果：E2处理可增加TEBs的数量、Ki-67蛋白和孕激素受体（PR）水平；这种治疗还使325个基因的表达改变了1.5倍以上。虽然3-MC单独处理对基因或蛋白质表达的影响很小，但当大鼠与3-MC和E2共同处理时，3-MC强烈抑制E2诱导的TEB发育、蛋白质合成和近一半E2诱导基因的表达。当使用8-PN作为ER配体时，3-MC的这种抑制作用部分反映出来。配体激活AHR的抗雌激素性至少部分是由于导管上皮细胞中ER α蛋白水平的降低。结论：我们的数据显示配体激活的AHR在乳腺er介导的过程中具有转录组范围的抗雌激素特性，从而解释了AHR配体的化学预防和内分泌干扰潜力。
BACKGROUND: Cross-talk between the aryl hydrocarbon receptor (AHR) and the estrogen receptor (ER) plays a major role in signaling processes in female reproductive organs.Objectives: We investigated the influence of the AHR ligand 3-methylcholanthrene (3-MC) on ER-mediated signaling in mammary gland tissue of ovariectomized (ovx) rats.METHODS: After 14 days of hormonal decline, ovx rats were treated for 3 days with 4 mu g/kg 17 beta-estradiol (E2), 15 mg/kg 8-prenylnaringenin (8-PN), 15 mg/kg 3-MC, or a combination of these compounds (E2 + 3-MC, 8-PN + 3-MC). Whole-mount preparations of the mammary gland were used to count terminal end buds (TEBs). Protein expression studies (immunohistochemistry, immunofluorescence), a cDNA microarray, pathway analyses, and quantitative real-time polymerase chain reaction (qPCR) were performed to evaluate the interaction between AHR- and ER-mediated signaling pathways.RESULTS: E2 treatment increased the number of TEBs and the levels of Ki-67 protein and progesterone receptor (PR); this treatment also changed the expression of 325 genes by more than 1.5-fold. Although 3-MC treatment alone had marginal impact on gene or protein expression, when rats were co-treated with 3-MC and E2, 3-MC strongly inhibited E2-induced TEB development, protein synthesis, and the expression of nearly half of E2-induced genes. This inhibitory effect of 3-MC was partially mirrored when 8-PN was used as an ER ligand. The anti-estrogenicity of ligand-activated AHR was at least partly due to decreased protein levels of ER alpha in ductal epithelial cells.CONCLUSION: Our data show transcriptome-wide anti-estrogenic properties of ligand-activated AHR on ER-mediated processes in the mammary gland, thereby contributing an explanation for the chemopreventive and endocrine-disrupting potential of AHR ligands.