Ah Receptor Regulation of Prostate Tumor Progression

描述(申请人提供)：芳烃受体(AhR)是一种转录因子，能结合氯化二恶英、其他外源化合物和各种内源性化学物质，并调节它们对包括前列腺在内的大多数器官的基因表达的影响。我们发现AhR信号通路可以极大地影响显性前列腺癌的发生。C57BL/6J背景的转基因小鼠前列腺癌(TRAMP)小鼠很少患肉眼前列腺癌(27只小鼠中有1只)，但它们的杂合(AhR+/-)和纯合(AhR-/-)AhR突变TRAMP兄弟姐妹迅速发展为大肿瘤(65只小鼠中27只和15只小鼠中10只)。然而，在缺乏traMP转基因的情况下，Ahr+/-或Ahr-/-小鼠中不会出现肿瘤。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可能是一个肿瘤抑制基因。拟议研究的一个目标是阐明AhR调节前列腺癌进展的机制。将系统地确定AhR基因对TRAMP小鼠的微观和宏观前列腺癌发展的影响。通过连续测定Ahr+/+、Ahr+/-和Ahr-/-TraMP小鼠中大T抗原、AhR和雄激素受体的表达，将检验导致肿瘤发病率差异的机制的假说。也可以进行AhR基因的杂合性丢失分析和雄激素受体基因等位基因数量的测量。主要的机制目标是验证AhR基因通过控制前列腺细胞的神经内分泌分化来控制前列腺癌进展的假说。这一假说是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形成之前，因此可能是决定低分化病变是否血管形成并随后发展为大肿瘤的关键的Ahr调节事件。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+/+流浪鼠。这两种SAhRM在体外都能抑制前列腺癌细胞的增殖。这些研究将阐明AhR信号通路在前列腺癌中作用的生化基础，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，在小鼠身上对这种新发现的前列腺癌AhR调节机制的研究可能会揭示能够控制人类前列腺癌进展(决定患有前列腺癌的男性是否患有这种疾病)的AhR相关机制。

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