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

• 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
• 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

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 已知芳烃受体（AhR）介导环境污染物的毒性， 二恶英和许多类似二恶英的化合物。由于在我们的环境中广泛发生， 由于这些污染物具有高毒性潜力，因此人们担心它们会促进包括乳腺癌在内的恶性肿瘤的发生。更 最近发现AhR也可能作为一种重要的受体蛋白参与肿瘤的发生 不依赖于外源性配体，其基于免疫耐受性和增加的癌症存活率 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的作用受到特定阻遏蛋白AhR阻遏物（AhRR）的限制。的 AhRR是一种配体非依赖性、转录失活的AhR样蛋白，被认为抑制AhR 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 明白我们建立了一个过表达AhRR的转基因小鼠（AhRR Tg小鼠）， 这些小鼠受到保护，不受二恶英诱导的致死性的影响， 应答炎症过程已经成为促进癌症发展的主要因素， 在TCDD诱导的肝脏炎症及其促肿瘤作用的情况下也显示了这种作用。 在我们理解AhRR如何调节AhR信号及其不良后果方面存在重大差距 导致失调的炎症反应和肿瘤促进的途径。初步数据显示， AhRR过表达抑制皮下注射后小鼠E0771乳腺癌细胞的肿瘤生长 挑战. AhRR Tg小鼠也部分保护免受细菌脂多糖（LPS）促进的 乳腺癌细胞的生长，表明其抑制炎症依赖性促进乳腺癌的潜力。 癌AhRR如何抑制AhR信号传导和炎症标志物的表达至关重要 以了解AhRR在乳腺肿瘤发生中的保护作用。我们的核心假设是AhRR将 在体内，其功能是对抗AhR在乳腺肿瘤形成中的作用。虽然AhRR已经在细胞中进行了研究， 尽管这种方法非常有前途，但目前尚不清楚它是否会在临床前小鼠模型中发挥所希望的作用。在这 在这方面，我们手头有一个新的资源，B6 AhRR转基因小鼠杂交到B6 PyMT品系， 适合研究乳腺癌的小鼠模型。根据我们的研究结果和现有文献，我们的总体 研究兴趣包括：（a）AhRR是否抑制体内乳腺肿瘤生长和/或进展， 炎症反应？(b)AhRR如何消除对凋亡的抵抗， 基因参与乳腺癌细胞，特别是如果AhR是由有毒的环境配体激活？ 本研究的设计将有助于了解AhR介导的乳腺癌细胞凋亡的途径和潜在的标记基因。 肿瘤发生和AhRR的抗炎作用和作为肿瘤抑制基因的功能。