Signaling Pathways in Stage of Mammary Tumorigenesis

申请人描述 乳腺癌现在是妇女死亡的第二大常见原因， 美国的为了改善这方面的预防和治疗方式， 乳腺癌的发病机制，包括： 环境和遗传因素。该项目基于 假设乳腺癌的发展和进展是一个 与导致细胞形成的分子变化相关的多阶段过程 获得恶性，然后具有侵袭性和转移性。在这 应用，在这个多步信号传导过程中的途径，导致乳腺癌 将阐明肿瘤形成。特别是，三个基因的作用 功能相互作用的系统将被确定：芳香族 碳氢化合物受体、CK 2和GSK 3激酶以及wnt信号通路， 和NF-κ B/Rel因子家族。项目1将评估 芳香烃受体/转录因子（AhR）在发展中的作用 乳腺肿瘤中AhR表达和功能的调控因素 信号传导，包括与NF-κ B的RelA亚基的相互作用。计划2 将继续研究调节丝氨酸苏氨酸激酶酪蛋白激酶 II（CK 2）和糖原合成酶激酶3（GSK 3）及其在wnt 信号通路和乳腺发育和转化。项目3 将表征NF-κ B/Rel转录因子的异常表达， 以及激酶如CK 2的作用，并阐明NF-κ B的功能作用。 激活乳腺肿瘤进展。所有这些项目将使 使用常见的模型系统，包括致癌剂处理的大鼠、转基因小鼠 在整个动物和人类乳腺癌组织中进行假设检验的模型 与人类疾病相关的标本。这些研究的结果 将提供关于环境与环境之间潜在联系的重要信息， 乳腺癌的发病率增加，这些因素的作用， 乳腺癌发病机制中的关键信号通路， 在新治疗中用作生物标志物或潜在治疗靶点 方式。

APPLICANT'S DESCRIPTION Breast cancer is now the second most frequent cause of death among women in the United States. To improve prevention and treatment modalities for this disease, one needs to understand the pathogenesis of breast cancer, including both environmental and genetic factors. This Program Project is based upon the hypothesis that the development and progression of breast cancer is a multistage process associated with molecular changes that result in cells acquiring malignant and then invasive and metastatic potential. In this application, pathways in this multistep signaling process leading to mammary tumor formation will be elucidated. In particular, the roles of three gene systems that functionally interact will be determined: the aromatic hydrocarbon receptor, the CK2 and GSK3 kinases and the wnt signaling pathway, and the NF-kB/Rel family of factors. Project 1 will evaluate the role of the aromatic hydrocarbon receptor/transcription factor (AhR) in the development of mammary tumors and examine factors controlling AhR expression and function in signaling, including interaction with the RelA subunit of NF-kB. Project 2 will pursue studies on the regulatory serine threonine kinases casein kinase II (CK2), and glycogen synthase kinase 3 (GSK3) and their roles in the wnt signaling pathway and in mammary development and transformation. Project 3 will characterize the aberrant expression of NF-kB/Rel transcription factors, and the role of kinases such as CK2, and elucidate the functional role of NF-kB activation in mammary tumor progression. All of these projects will make use of common model systems including carcinogen-treated rats, trangenic mouse models for hypothesis testing in whole animals, and human breast cancer tissue specimens for correlation with human disease. The results of these studies will provide important information on the potential link between environmental factors and increased incidence of breast cancer, on the roles of these critical signaling pathways in the pathogenesis of breast cancer, and on their use as biomarkers or potential therapeutic targets in novel treatment modalities.