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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 TCDD（Dioxin）是一种工业副产品和环境污染物，是最有效的合成毒物，引起致长，免疫调节和促进肿瘤的活性。 对TCDD的反应是通过芳香族烃（或二恶英）受体（AHR）介导的，该受体是配体激活的碱性螺旋 - 环螺旋（BHLH）转录因子。 TCDD与其受体的结合，导致许多基因的表达增强，包括细胞增殖和分化。 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与这些细胞的恶性肿瘤直接上调。我们的新发现促使我们假设AHR过表达在HBC的发展中起作用。我们将旨在确定某些因素，以侵入性和转移性表型的肿瘤细胞向正常上皮细胞的转换和转换。 为了解决一个问题，即单独的AHR过表达是否足以改变正常的乳腺上皮，以及它是否与转化有因果关系相关，我们将使用两种遗传方法。 到 直接解决了AHR表达增加的影响，在正常的乳腺上皮中，人类AHR cDNA将稳定转染和过表达。 AHR转换线中转移性表型的发展将被分析，以作为其在软琼脂培养基中与锚固无关增长的能力以及 诱导裸鼠肿瘤。 相反，通过将靶向人AHR的siRNA转染以证明AHR在修饰转移的进展中的直接作用，将AHR表达在高肿瘤HBC细胞系中被阻断。 尽管AHR已在其结合和介导多环芳烃和有机氯的毒性的背景下进行了鉴定和研究，但有证据表明在正常细胞功能中提出了其他作用。 新颖的观察结果，这是我们提出的研究的基础，进一步指出 AHR的另一个病态生理作用。 总之，我们提出的研究将解决乳腺癌研究的研究研究。 即使有最佳的结果，我们提出的研究也将确定AHR是乳腺癌进展的关键调节剂。 建立后，AHR可以用作独立的预后因素，也可以用作早期生物标志物来确定可能早期干预的癌症进展程度。