The protective role of the AhR Repressor in breast cancer development

摘要/摘要 芳香烃受体(AhR)是已知的介导环境污染物毒性的物质，如 二恶英和许多二恶英类化合物。由于我们的环境和环境中普遍存在的 这些污染物具有很高的毒性，会促进包括乳腺癌在内的恶性肿瘤的发生。更多 最近研究发现，AhR也可能作为一种重要的受体蛋白参与肿瘤的发生发展。 不依赖外源配体，这是基于免疫耐受和提高癌症患者的存活率 细胞。因此，AhR已成为癌症治疗新药的一个有吸引力的靶点。 此外，AhR的作用受到一种特定的抑制蛋白-AhR抑制蛋白(AHRR)的限制。这个 AHRR是一种不依赖配体的转录失活的AhR样蛋白，被认为能抑制AhR 发信号。虽然AHRR有效地阻断了AhR，但AHRR作为肿瘤抑制基因的作用很差 明白了。我们建立了一种过表达AHRR的转基因小鼠(AHRR TG小鼠)，并发现 这些小鼠受到保护，免受二恶英诱导的致死与减少炎症有关 回应。炎症过程已经成为促进癌症发展的一个主要因素，它 在TCDD诱导的肝脏炎症及其促进肿瘤作用的情况下也显示了这一点。 在我们对AHRR如何调节AhR信号及其不利结果的理解上存在重大差距 导致非调节性炎症反应和肿瘤促进的途径。初步数据显示， AHRR过表达抑制小鼠乳腺癌E0771皮下移植瘤生长 挑战。AHRR转基因小鼠对细菌脂多糖(LPS)刺激也有部分保护作用 乳腺癌细胞的生长表明其有可能抑制炎症依赖的乳房促进作用 癌症。AHRR如何抑制AhR信号和炎症标志物的表达至关重要 为了解AHRR在乳腺肿瘤发生中的保护作用。我们的中心假设是AHRR将 在体内发挥作用，以对抗AhR在乳腺肿瘤形成中的作用。虽然AHRR已经在细胞和 非常有希望，但目前还不知道它是否会在临床前小鼠模型中发挥希望的作用。在这 在这方面，我们手头有一个新的资源，B6AHRR转基因小鼠杂交到B6PYMT品系，a 适合研究乳腺癌的小鼠模型。根据我们的结果和目前的文献，我们的总体 兴趣包括：(A)AHRR是否在体内抑制乳腺肿瘤的生长和/或进展 炎症反应？(B)AHRR如何消除对凋亡的抵抗，以及哪些抗凋亡药物 基因与乳腺癌细胞有关，特别是当AhR被有毒的环境配体激活时？ 本研究设计将有助于理解AhR介导的乳腺通路和潜在的标记基因 肿瘤的发生与AHRR的抗炎作用和作为肿瘤抑制基因的功能。

Summary/Abstract The aryl hydrocarbon receptor (AhR) is known for mediating the toxicity of environmental pollutants such as dioxins and numerous dioxin-like compounds. Due to the widespread occurrence in our environment and the high toxic potential, these contaminants are of concern to promote malignancies including breast cancer. More recently it has been found that the AhR may also act as a critical receptor protein in tumor promotion independent from exogenous ligands, which is based on immune tolerance and increased survival in cancer cells. Consequently, the AhR has emerged as an attractive target for new drugs in cancer therapy. Furthermore, the AhR's action is restricted by a specific repressor protein, the AhR Repressor (AhRR). The AhRR is a ligand-independent, transcriptionally inactive AhR-like protein and is thought to repress AhR signaling. While AhRR effectively blocks AhR, the role of AhRR as a tumor suppressor gene is only poorly understood. We established a transgenic mouse (AhRR Tg mice) that overexpresses AhRR and discovered that these mice were protected from dioxin-induced lethality associated with a reduction in inflammatory responses. Inflammatory processes have emerged as a major factor promoting cancer development, which has been shown also in the case of TCDD-induced liver inflammation and its tumor promoting effects. Significant gaps exist in our understanding how the AhRR regulates AhR signaling and its adverse outcome pathways leading to deregulated inflammatory responses and tumor promotion. Preliminary data show that overexpression of AhRR suppresses tumor growth of E0771 breast cancer cells in mice after subcutaneous challenge. AhRR Tg mice were also partially protected against bacterial lipopolysaccharide- (LPS) promoted growth of breast cancer cells indicating its potential to suppress inflammatory-dependent promotion of breast cancer. How the AhRR inhibits AhR signaling and expression of inflammatory markers is of critical importance in order to understand AhRR's protective role in breast tumorigenesis. Our central hypothesis is that AhRR will function, in vivo, to oppose AhR's role in mammary tumor formation. While AhRR has been studied in cells and is very promising, it is not yet known whether it will function as hoped in a pre-clinical mouse model. In this regard, we have at hand a novel resource, the B6 AhRR transgenic mouse crossed into the B6 PyMT strain, a suitable mouse model to study breast cancer. Based on our results and the current literature, our overarching interests include: (a) Does the AhRR suppress mammary tumor growth and/or progression in vivo and repress inflammatory responses? (b) How does the AhRR abolish resistance to apoptosis and what anti-apoptotic genes are involved in breast cancer cells, particularly if the AhR is activated by toxic environmental ligands? This study design will help to understand the pathway and potential marker genes of AhR-mediated mammary tumorigenesis and AhRR's anti-inflammatory role and function as a tumor suppressor gene.