Cancer Biology Graduate Interdisciplinary Program, The University of Arizona, Tucson, AZ 85724, USA.
The University of Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA.
Nutrients. 2019 Oct 23;11(11):2559. doi: 10.3390/nu11112559.
Triple negative breast cancers (TNBC) are the most aggressive and lethal breast cancers (BC). The aryl hydrocarbon receptor (AHR) is often overexpressed in TNBC, and its activation results in the epigenetic silencing of , which is a necessary factor for the transcriptional activation of estrogen receptor (ER)α. The dietary isoflavone genistein (GEN) modulates CpG methylation in BC cells. The purpose of this study was to investigate the effect of GEN on epigenetic regulation and AHR activity in vivo and TNBC cells. Mice were administered a control or GEN-enriched (4 and 10 ppm) diet from gestation through post-natal day 50. Mammary tissue was analyzed for changes in regulation and AhR activity. TNBC cells with constitutively hypermethylated (HCC38) and MCF7 cells were used. Protein levels and mRNA expression were measured by Western blot and real-time PCR, respectively. promoter occupancy and CpG methylation were analyzed by chromatin immunoprecipitation and methylation-specific PCR, respectively. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. GEN administered in the diet dose-dependently decreased basal methylation and AHR activity in the mammary gland of adult mice. HCC38 cells were found to overexpress constitutively active AHR in parallel with hypermethylation. The treatment of HCC38 cells with GEN upregulated BRCA1 protein levels, which was attributable to decreased CpG methylation and AHR binding at exon 1a. In MCF7 cells, GEN prevented the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-dependent localization of AHR at the gene. These effects were consistent with those elicited by control AHR antagonists galangin (GAL), CH-223191, and α-naphthoflavone. The pre-treatment with GEN sensitized HCC38 cells to the antiproliferative effects of 4-hydroxytamoxifen. We conclude that the dietary compound GEN may be effective for the prevention and reversal of AHR-dependent hypermethylation, and the restoration of ERα-mediated response, thus imparting the sensitivity of TNBC to antiestrogen therapy.
三阴性乳腺癌（TNBC）是最具侵袭性和致命性的乳腺癌。芳香烃受体（AHR）在 TNBC 中常过度表达，其激活导致必需的雌激素受体（ER）α转录激活因子 失活。膳食异黄酮染料木黄酮（GEN）可调节乳腺癌细胞中的 CpG 甲基化。本研究旨在研究 GEN 对体内和 TNBC 细胞中 表观遗传调控和 AHR 活性的影响。从妊娠到产后第 50 天，给予小鼠对照或 GEN 富集（4 和 10ppm）饮食。分析乳腺组织中 调节和 AhR 活性的变化。使用具有组成型高甲基化 （HCC38）和 MCF7 细胞的 TNBC 细胞。通过 Western blot 和实时 PCR 分别测量蛋白质水平和 mRNA 表达。通过染色质免疫沉淀和甲基化特异性 PCR 分别分析 启动子占据和 CpG 甲基化。通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）测定细胞活力。饮食中给予 GEN 呈剂量依赖性降低成年小鼠乳腺中的基础 甲基化和 AHR 活性。发现 HCC38 细胞与 过度甲基化平行表达组成型激活的 AHR。GEN 处理 HCC38 细胞可上调 BRCA1 蛋白水平，这归因于 外显子 1a 的 CpG 甲基化和 AHR 结合减少。在 MCF7 细胞中，GEN 阻止了 2,3,7,8-四氯二苯并-p-二恶英（TCDD）依赖的 AHR 在 基因上的定位。这些作用与对照 AHR 拮抗剂金雀异黄素（GAL）、CH-223191 和 α-萘黄酮引起的作用一致。GEN 的预处理使 HCC38 细胞对 4-羟基他莫昔芬的增殖抑制作用敏感。我们得出结论，膳食化合物 GEN 可能有效预防和逆转 AHR 依赖性 过度甲基化，并恢复 ERα 介导的反应，从而使 TNBC 对抗雌激素治疗敏感。
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