Ah Receptor Regulation of Prostate Tumor Progression

描述（由申请人提供）：芳烃受体（AhR）是一种转录因子，可结合氯化二恶英、其他异种生物和各种内源性化学物质，并介导其对大多数器官（包括前列腺）基因表达的影响。我们已经发现AhR信号通路可以极大地影响显性前列腺癌的发病率。C57BL/6J基因的转基因腺癌小鼠前列腺（TRAMP）小鼠很少发生肉眼可见的前列腺癌（27只小鼠中有1只），但其杂合子（Ahr +/-）和纯合子（Ahr -/-） Ahr突变的TRAMP兄弟姐妹迅速发生大肿瘤（65只小鼠中有27只和15只小鼠中分别有10只）。然而，在缺乏TRAMP转基因的Ahr +/-或Ahr -/-小鼠中没有发生肿瘤。这些初步结果表明，AhR可以显著影响前列腺癌的进展阶段，并提示AhR可能是一种肿瘤抑制基因。拟议研究的一个目的是阐明AhR调节前列腺肿瘤进展的机制。Ahr基因型对TRAMP小鼠微观和宏观前列腺癌发展的影响将被系统地确定。通过在AhR +/+、AhR +/-和AhR -/- TRAMP小鼠中依次测定大T抗原、AhR和雄激素受体的表达，将对导致这些肿瘤发生率差异的机制假设进行检验。AhR基因的失杂合性分析和雄激素受体基因等位基因数目的测定也可以进行。主要的机制目的是验证Ahr基因型通过控制前列腺细胞的神经内分泌分化来控制前列腺肿瘤进展的假设。该假设基于基因表达分析和免疫组织化学定位研究的初步结果，即神经内分泌分化发生在低分化结节血管化之前，因此可能是ahr调节的关键事件，决定低分化病变是否血管化并随后发展为大肿瘤。最终目的是验证选择性AhR调节剂(SAhRMs) - 6-甲基- 1,3,8-三氯二苯并呋喃（6-MCDF）和吲哚- 3-甲醇-可以抑制或预防前列腺癌的假设。这些实验将使用标准C57BL/6 x FVB背景下的Ahr +/+TRAMP小鼠。两种SAhRMs均能抑制前列腺癌细胞的体外增殖。这些研究将阐明AhR信号通路对前列腺癌作用的生化基础，并开始SAhRMs的体内试验，作为治疗前列腺癌的一种可能的新治疗策略。对人类健康的潜在影响是，对这种新发现的小鼠前列腺AhR调节机制的研究可能揭示能够控制前列腺肿瘤进展的AhR相关机制（这决定了患有前列腺癌的男性是否患有这种疾病或死于这种疾病）

DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AhR) is a transcription factor that binds chlorinated dioxins, other xenobiotics, and various endogenous chemicals and mediates their effects on gene expression in most organs, including prostate. We have discovered that the AhR signaling pathway can greatly affect the incidence of overt prostate cancer. Transgenic adenocarcinoma mouse prostate (TRAMP) mice on a C57BL/6J background rarely develop macroscopic prostate cancer (1 of 27 mice), but their heterozygous (Ahr +/-) and homozygous (Ahr -/-) AhR mutant TRAMP siblings rapidly develop large tumors (27 of 65 and 10 of 15 mice, respectively). Yet no tumors occur in Ahr +/- or Ahr -/- mice in the absence of the TRAMP transgene. These preliminary results demonstrate that the AhR can greatly affect the progression phase of prostate cancer, and suggest that Ahr may be a tumor suppressor gene. One objective of the proposed research is to elucidate mechanisms by which AhR regulates prostate tumor progression. Effects of Ahr genotype on microscopic and macroscopic prostate cancer development in TRAMP mice will be systematically determined. Hypotheses about the mechanisms responsible for these differences in tumor incidence will be tested by sequentially determining large T antigen, AhR, and androgen receptor expression in Ahr +/+, Ahr +/-, and Ahr -/- TRAMP mice. Loss of heterozygosity analysis on the AhR gene and measurements of androgen receptor gene allele number may also be conducted. The primary mechanistic objective is to test the hypothesis that Ahr genotype, controls prostate tumor progression by controlling neuroendocrine differentiation of prostatic cells. This hypothesis is based on preliminary results from gene expression analysis and immunohistochemical localization studies that neuroendocrine differentiation occurs before poorly differentiated nodules vascularize and therefore may be the key Ahr-regulated event that determines whether poorly differentiated lesions will vascularize and subsequently develop into large tumors. The final objective is to test the hypothesis that selective AhR modulators (SAhRMs) - 6-methyl- 1,3,8-trichlorodibenzofuran (6-MCDF) and indole- 3-carbinol - can inhibit or prevent prostate cancer. These experiments will use Ahr +/+TRAMP mice on the standard C57BL/6 x FVB background. Both SAhRMs inhibit prostate cancer cell proliferation in vitro. The proposed studies will elucidate the biochemical basis for effects of the AhR signaling pathway on prostate cancer and begin the in vivo testing of SAhRMs as a possible new therapeutic strategy for treating this disease. The potential impact on human health is that studies on this newly discovered prostate AhR regulatory mechanism in mice may shed light on AhR-related mechanisms capable of controlling prostate tumor progression (which determines whether men with prostate cancer live with or die from this disease) in humans