The Aryl Hydrocarbon Receptor and Breast Cancer

描述（由申请人提供）：我们的目标是研究芳烃受体（AhR）在乳腺癌进展中的作用，长期目标是针对AhR进行乳腺癌的预防和治疗干预。AhR是一种介导环境多环芳烃（PAH）致癌作用的配体激活转录因子。PAH激活AhR通过诱导CYP1家族基因，随后产生反应性代谢物和转录因子的激活，与致癌有关。我们的实验室和其他实验室已经报道了在晚期人类乳腺癌中组成型活化AhR的高水平表达。我们进一步发现，AhR的异位过表达足以诱导人乳腺上皮细胞（HMEC）的恶性转化，而不依赖于PAH。我们生成的ahr转化的HMEC克隆细胞系在体外测量中表现出增强的增殖，上皮到间质转化以及增强的迁移和侵袭性。因此，我们假设AhR的表达升高与乳腺癌的进展相关，并且AhR的高表达通过上调对肿瘤生存和侵袭性至关重要的信号通路来促进浸润性乳腺癌的发展。为了解决这一假设，我们的具体目标是：1)使用SCID小鼠异种移植模型测试AhR过表达与体内浸润性癌发生和进展的相关性；通过原位植入过表达AhR的克隆HMEC细胞系，并证明其形成乳腺肿瘤和转移性隐匿物的能力2)通过siRNA敲低过表达AhR的细胞中AhR的表达，然后在体外和SCID小鼠中评估其致瘤潜力，来研究AhR过表达对侵袭性癌发生和进展的因果作用3)确定哪些基因和信号通路被激活肿瘤进展AhR过表达；4)利用组织微阵列技术将人类乳腺肿瘤中AhR的表达与疾病分期及其他预后生物标志物相关联，研究AhR的表达是否在晚期人类乳腺癌中普遍上调。拟议的研究将确定AhR在浸润性乳腺癌进展中的因果作用。我们的研究结果可能验证了AhR作为一种新的预测临床标志物和设计用于转移性乳腺癌治疗干预的新型选择性抑制剂的独特靶点。

DESCRIPTION (provided by applicant): Our objective is to investigate the role of the aryl hydrocarbon receptor (AhR) in breast cancer progression with a long-term goal of targeting AhR for preventive and therapeutic intervention of breast cancer. AhR is a ligand- activated transcription factor which mediates the carcinogenic effects of environmental polycyclic aromatic hydrocarbons (PAH). PAH activation of AhR is implicated in carcinogenesis through induction of CYP1 family of genes with subsequent generation of reactive metabolites and activation of transcription factors. Our laboratory and others have reported high-level expression of constitutively activated AhR in advanced human breast carcinomas. We further showed that ectopic over expression of AhR is sufficient to induce malignant transformation of human mammary epithelial cells (HMEC), independent of PAH. Our generated clonal cell lines of the AhR-transformed HMEC exhibited enhanced proliferation, epithelial-to-mesenchymal transition and enhanced migration and invasiveness, as measured in vitro. We therefore postulated that elevated expression of AhR correlates with and forecasts breast cancer progression and that high AhR expression promotes the development of invasive breast carcinoma by up-regulating signaling pathways critical for tumor survival and invasiveness. To address this hypothesis our specific aims are 1) To test the relevance of AhR over expression for development and progression of invasive carcinoma in vivo using SCID mice xenograft model, by orthotopically implanting clonal HMEC cell lines which over express AhR and demonstrating their ability to form mammary tumors and metastatic occults 2) To examine the causal role of the AhR over expression on the development and progression of invasive carcinoma by the siRNA knockdown of AhR expression in cells overexpressing AhR followed by assessing their tumorigenic potential in vitro and in SCID mice 3) To determine which genes and signaling pathways for tumor progression are activated by AhR over expression; 4) To examine whether the expression of AhR is universally upregulated in advanced human breast cancer, by correlating the AhR expression in human breast tumors with the stage of the disease and other prognostic biomarkers using tissue microarrays. The proposed research will define the causal role of AhR in invasive breast cancer progression. Our findings may validate the AhR as a new predictive clinical marker and a unique target for designing novel selective inhibitors for therapeutic intervention of metastatic breast cancer.