The protective role of the AhR Repressor in breast cancer development

AhR 阻遏物在乳腺癌发展中的保护作用

基本信息

批准号：
9918372
负责人：
CHRISTOPH F A VOGEL
金额：
$ 19.63万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918372
关键词：
AHR gene ARNT gene ARNT protein Affect Anti-Inflammatory Agents Antigens Apoptosis Apoptotic Aryl Hydrocarbon Receptor Biological Assay Breast Cancer Cell Breast Cancer Model Breast Cancer therapy Breast Carcinogenesis Breast Epithelial Cells Breast cancer metastasis CXCL1 gene Cells Cyclic AMP-Dependent Protein Kinases Data Development Dioxins Endocrine Environment Environmental Exposure Environmental Pollutants Exhibits Exposure to Future Genes Genetic Transcription Goals Growth Hand Health Immune Tolerance Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Lead Ligands Lipopolysaccharides Literature Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Mediator of activation protein Metastatic breast cancer Modeling Mus PRKCA gene Pathway interactions Play Polyomavirus Process Property Proteins Receptor Signaling Regulation Repressor Proteins Research Design Resistance Resources Role Subcutaneous Injections Testing Tetrachlorodibenzodioxin Tissues Toxic effect Transgenic Mice Transplantation Tumor Promotion Tumor Suppressor Genes Tumor Suppressor Proteins Xenograft procedure adverse outcome base breast tumorigenesis cancer cell cancer therapy carcinogenesis cyclooxygenase 2 enzyme activity experimental study in vivo inflammatory marker innovation insight interest liver inflammation malignant breast neoplasm mammary epithelium mouse model neoplastic cell new therapeutic target novel overexpression pollutant pre-clinical protein activation receptor receptor binding receptor expression relB protein response subcutaneous toxicant tumor tumor growth

项目摘要

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.

摘要/摘要芳烃受体 (AhR) 因介导环境污染物的毒性而闻名，例如二恶英和许多二恶英类化合物。由于在我们的环境中广泛存在，这些污染物具有高毒性，可能会促进包括乳腺癌在内的恶性肿瘤。更多的最近发现AhR也可能作为肿瘤促进的关键受体蛋白独立于外源配体，其基于免疫耐受和癌症存活率的提高细胞。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 的作用受到特定阻遏蛋白，即 AhR 阻遏蛋白 (AhRR) 的限制。这 AhRR 是一种不依赖配体、转录失活的 AhR 样蛋白，被认为可以抑制 AhR 发信号。虽然 AhRR 有效阻断 AhR，但 AhRR 作为抑癌基因的作用很差明白了。我们建立了过度表达 AhRR 的转基因小鼠（AhRR Tg 小鼠）并发现这些小鼠受到保护，免受二恶英诱导的死亡，与炎症减少有关回应。炎症过程已成为促进癌症发展的主要因素，其中 TCDD 引起的肝脏炎症及其促进肿瘤的作用也得到了证实。我们对 AhRR 如何调节 AhR 信号传导及其不良后果的理解存在重大差距导致炎症反应失调和肿瘤促进的途径。初步数据表明 AhRR 过表达可抑制小鼠皮下注射后 E0771 乳腺癌细胞的肿瘤生长挑战。 AhRR Tg 小鼠也受到部分保护，免受细菌脂多糖（LPS）促进乳腺癌细胞的生长表明其具有抑制炎症依赖性乳腺癌促进作用的潜力癌症。 AhRR 如何抑制 AhR 信号传导和炎症标志物的表达至关重要为了了解 AhRR 在乳腺肿瘤发生中的保护作用。我们的中心假设是 AhRR 将在体内的功能是对抗 AhR 在乳腺肿瘤形成中的作用。虽然 AhRR 已在细胞中进行了研究，非常有前途，但尚不清楚它是否会在临床前小鼠模型中发挥预期的作用。在这个考虑到，我们手头上有一种新的资源，B6 AhRR 转基因小鼠与 B6 PyMT 品系杂交，适合研究乳腺癌的小鼠模型。根据我们的结果和当前的文献，我们的总体兴趣包括：(a) AhRR 是否在体内抑制乳腺肿瘤生长和/或进展并抑制炎症反应？ (b) AhRR如何消除细胞凋亡抗性以及什么抗细胞凋亡基因与乳腺癌细胞有关，特别是当 AhR 被有毒环境配体激活时？本研究设计将有助于了解 AhR 介导的乳腺的途径和潜在标记基因肿瘤发生和 AhRR 的抗炎作用以及作为抑癌基因的功能。