Ah Receptor Regulation of Prostate Tumor Progression

Ah 受体对前列腺肿瘤进展的调节

• 批准号: 7065199
• 负责人: RICHARD Eugene PETERSON
• 金额: $ 22.38万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-21 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7065199
• 关键词: androgen receptor; aromatic hydrocarbon receptor; biological signal transduction; cancer prevention; cell differentiation; chromogranins; gene expression; genetic regulation; genetically modified animals; genotype; histology; immunocytochemistry; indoles; laboratory mouse; lymph nodes; neoplasm /cancer genetics; neoplastic process; neuroendocrine system; neuropilins; polychlorodibenzofuran; prostate neoplasms; transfection /expression vector

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

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、其他外源性化学物质和各种内源性化学物质，并介导它们对大多数器官（包括前列腺）基因表达的影响。我们发现AhR信号通路可以极大地影响前列腺癌的发病率。 C57BL/6J 背景的转基因腺癌​​小鼠前列腺 (TRAMP) 小鼠很少发展为肉眼可见的前列腺癌（27 只小鼠中的 1 只），但它们的杂合子 (Ahr +/-) 和纯合子 (Ahr -/-) AhR 突变体 TRAMP 兄弟姐妹迅速发展为大型前列腺癌肿瘤（分别为 65 只小鼠中的 27 只和 15 只小鼠中的 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可以极大地影响前列腺癌的进展阶段，并表明Ahr可能是一种抑癌基因。拟议研究的目标之一是阐明 AhR 调节前列腺肿瘤进展的机制。将系统地确定 Ahr 基因型对 TRAMP 小鼠微观和宏观前列腺癌发展的影响。将通过连续测定 Ahr +/+、Ahr +/- 和 Ahr -/- TRAMP 小鼠中大 T 抗原、AhR 和雄激素受体表达来测试有关肿瘤发生率差异的机制的假设。还可以进行AhR基因的杂合性丢失分析和雄激素受体基因等位基因数的测量。主要机制目标是检验 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。这一假设基于基因表达分析和免疫组化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，因此可能是决定低分化病变是否会血管化并随后发展为大肿瘤的关键Ahr调节事件。最终目标是检验选择性 AhR 调节剂 (SAhRM) - 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。这些实验将在标准 C57BL/6 x FVB 背景上使用 Ahr +/+TRAMP 小鼠。两种 SAhRM 均可在体外抑制前列腺癌细胞增殖。拟议的研究将阐明 AhR 信号通路对前列腺癌影响的生化基础，并开始对 SAhRM 作为治疗这种疾病的可能新治疗策略进行体内测试。对人类健康的潜在影响是，对小鼠中这种新发现的前列腺 AhR 调节机制的研究可能会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）人类