ROLE OF THE ARYL HYDROCARBON RECEPTOR IN BREAST CANCER

芳基烃受体在乳腺癌中的作用

• 批准号: 8166235
• 负责人: Sakina Elzebair Eltom
• 金额: $ 12.66万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-08 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166235
• 关键词: Address; Agar; Anchorage-Independent Growth; Area; Aromatic Hydrocarbons; Aromatic Polycyclic Hydrocarbons; Aryl Hydrocarbon Receptor; BHLH Protein; Binding; Biological Assay; Biological Markers; Breast Carcinoma; Cell Line; Cell Proliferation; Cell physiology; Cells; Chlorinated Hydrocarbons; Complementary DNA; Computer Retrieval of Information on Scientific Projects Database; Development; Dioxins; Early treatment; Environmental Pollutants; Epithelial; Funding; Genes; Genetic; Grant; Human; Institution; Investigation; Ligands; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Neoplasm Metastasis; Normal Cell; Nude Mice; Outcomes Research; Phenotype; Physiological; Play; Prognostic Factor; Proteins; Research; Research Personnel; Resources; Role; Small Interfering RNA; Source; Tetrachlorodibenzodioxin; Toxic effect; United States National Institutes of Health; anticancer research; base; malignant breast neoplasm; mammary epithelium; neoplastic cell; novel; overexpression; receptor; response; toxicant; tumor; tumor progression; tumorigenic

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. TCDD (dioxin), an industrial byproduct and environmental pollutant is the most potent synthetic toxicant that elicits teratogenic, immuno-modulating, and tumor-promoting activities. The responses to TCDD are mediated via the aromatic hydrocarbon (or dioxin) receptor (AhR), which is a ligand-activated basic helix-loop-helix (bHLH) transcription factor. Binding of TCDD to its receptor, results in enhanced expression of many genes including those are involved in cellular proliferation and differentiation. Our preliminary investigation on the expression of the AhR protein in human breast carcinoma (HBC) cell lines has revealed that the AhR is dramatically upregulated in direct proportion to the malignancy of these cells. Our novel findings prompted us to hypothesize that AhR over-expression plays a role in the progression of HBC. We will aim to identify some factors responsible for the disregulation and the switch of normal epithelial to tumor cells with invasive and metastatic phenotype. To address the question of whether the AhR overexpression alone is sufficient for transforming normal mammary epithelia, and whether it is causally associated with transformation, we will use two genetic approaches. To directly address the effect of increased expression of AhR, the human AhR cDNA will be stably transfected and over-expressed in a normal mammary epithelia. The development of metastatic phenotypes in the AhR-transformed lines will be assayed as their ability for anchorage-independent growth in soft agar media and for inducing tumors in nude mice. Conversely, the AhR expression will be blocked in high tumorigenic HBC cell lines by transfecting siRNA targeting human AhR to demonstrate a direct role of the AhR in modifying the progression of metastasis. Although the AhR has been identified and studied in the context of its binding and mediating the toxicity of polycyclic aromatic hydrocarbons and organochlorines, evidence are gathering to suggest other role(s) for it in normal cell function. The novel observations, which are the basis of our proposed studies further point to another patho-physiological role for AhR. In conclusion, our proposed studies will address an understudied area of breast cancer research. Even with an optimum outcome, the research we are proposing will identify the AhR as a key regulator in breast cancer progression. When established, the AhR could be used as an independent prognostic factor, and possibly as an early biomarker for determining the degree of cancer progression for possible early intervention.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 TCDD（二恶英）是一种工业副产品和环境污染物，是最有效的合成毒物，具有致畸、免疫调节和促肿瘤活性。 对 TCDD 的反应是通过芳香烃（或二恶英）受体 (AhR) 介导的，它是一种配体激活的碱性螺旋-环-螺旋 (bHLH) 转录因子。 TCDD 与其受体结合，导致许多基因的表达增强，包括那些参与细胞增殖和分化的基因。 我们对表达的初步调查 人类乳腺癌 (HBC) 细胞系中的 AhR 蛋白表明，AhR 的显着上调与这些细胞的恶性程度成正比。我们的新发现促使我们假设 AhR 过度表达在 HBC 的进展中发挥作用。我们的目标是确定一些导致正常上皮细胞失调和转变为具有侵袭性和转移表型的肿瘤细胞的因素。 为了解决单独的 AhR 过表达是否足以转化正常乳腺上皮，以及它是否与转化有因果关系的问题，我们将使用两种遗传方法。 到 直接解决AhR表达增加的影响，人AhR cDNA将被稳定转染并在正常乳腺上皮细胞中过表达。 AhR 转化系中转移表型的发展将通过其在软琼脂培养基中不依赖贴壁生长的能力和 在裸鼠中诱导肿瘤。 相反，通过转染针对人 AhR 的 siRNA，可阻断高致瘤性 HBC 细胞系中的 AhR 表达，以证明 AhR 在改变转移进展中的直接作用。 尽管 AhR 已在其结合和介导多环芳烃和有机氯的毒性方面得到鉴定和研究，但越来越多的证据表明它在正常细胞功能中的其他作用。 作为我们提出的研究基础的新观察进一步指出 AhR 的另一个病理生理作用。 总之，我们提出的研究将涉及乳腺癌研究的一个未充分研究的领域。 即使获得最佳结果，我们提议的研究也将确定 AhR 是乳腺癌进展的关键调节因子。 一旦建立，AhR 可用作独立的预后因素，并且可能作为早期生物标志物来确定癌症进展程度，以便进行可能的早期干预。