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Experimental Modeling of Human Breast Cancer in Mice

人类乳腺癌小鼠实验模型

基本信息

批准号：
7914908
负责人：
HALLGEIR RUI
金额：
$ 14.87万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7914908
关键词：
Adjuvant Antibodies Antineoplastic Agents Apoptotic Arts Biochemical Biology Breast Breast Cancer Cell Breast Cancer Model Cancer Patient Cancer cell line Cell Line Cell Survival Cells Cessation of life Clinic Clinical Clinical Treatment Clinical Trials Complement Data Development Differentiation and Growth Doxorubicin Endocrine Engineering Environment Epithelial Epithelial Cells Evaluation Expenditure Experimental Models Goals Government Growth Histology Homebound Persons Hormonal Hormones Human In Situ In Vitro Institution Laboratories Malignant Neoplasms Mammary gland Medical Medicine Methods Modeling Mus Neoplasm Metastasis Paclitaxel Pain Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phosphorylation Physiological Pituitary Hormones Postmenopause Pre-Clinical Model Preclinical Testing Premenopause Primary Neoplasm Prolactin Prolactin Receptor Protein Tyrosine Kinase Proteins RNA Interference Receptor Signaling Research Resources Role Serum Signal Pathway Signal Transduction Stimulus Testing Therapeutic Agents Tissue Microarray Tissues Transplantation Tumor Cell Line United States National Institutes of Health Woman Work antitumor agent antitumor drug autocrine base breast cancer diagnosis cancer cell cancer therapy clinical efficacy density drug candidate drug sensitivity drug testing efficacy testing expectation improved in vivo inhibitor/antagonist insight knock-down malignant breast neoplasm mouse model mutant novel pre-clinical prevent receptor response therapeutic target tumor

项目摘要

Project Summary Despite enormous expenditures and efforts by academic, government, and pharmaceutical institutions, most drugs that show promise against human breast cancer in preclinical testing in mice, fail to cure breast cancer in the clinic. There is a great need for improved drug response-predictive testing of human breast cancer in the preclinical setting to identify the best drug candidates. Based on novel insight gained in our laboratories, as a key first step we propose to correct the mouse endocrine environment to more adequately mimic the endocrine environment of breast cancer patients. Novel and independent insight from the two collaborating laboratories suggest that prolactin acts as a modulator of drug sensitivity in human breast cancer. Prolactin receptors are expressed, often at elevated levels, in a majority of human breast cancers. However, current mouse models are inadequate since mouse prolactin prevents activation of human prolactin receptors. Thus, current predictive testing of drugs against human breast cancer is performed on human breast cancer lines selected for growth under prolactin-free conditions. We will now test the role of prolactin as a modulator of breast cancer drug sensitivity and biology. For this study, a mouse model that expresses physiological levels of human prolactin has been genetically engineered for more accurate predictive testing of drugs on human breast cancer xenotransplants. The central hypothesis is that PRL receptor signaling, through its effects on mammary cell survival, growth, and differentiation, modulates sensitivity of breast cancer cells to anti-tumor agents. Consistent with this, we further hypothesize that mice, in which endogenous mouse prolactin has been replaced with physiological levels of human prolactin, will restore prolactin receptor signaling in human breast cancer xenotransplants and provide a more relevant endocrine environment for improved prediction of clinical responsiveness of breast cancer to therapeutic agents. Finally, we hypothesize that the hPRL expressing mice will allow us to establish new and transplantable breast cancer lines that more closely resemble primary breast human cancer than existing metastasis-derived tumor cell lines. If successful, the new mouse model would be available for testing of a broad number of human breast cancer drug candidates, with the potential for more reliable prediction of clinical efficacy. In addition, successful transplantation of primary breast cancer tissue with epithelial and stromal components will pave the road to a new personalized medicine approach to treatment of breast cancer patients. Project Narrative Most drugs that work when tested on human breast cancer in mice, fail to cure breast cancer in humans. There is a great need to improve the ability to predict whether candidate breast cancer drugs will work in patients. To this end, we have developed a new mouse model with a hormone environment that more closely resembles that of breast cancer patients. We will test the hypothesis that the new mouse represents an improved preclinical model for more accurate predictive testing of breast cancer drug candidates.

项目摘要尽管学术、政府和制药机构投入了巨大的资金和努力，但大多数在小鼠的临床前试验中显示出抗人乳腺癌药物的前景，但未能治愈乳腺癌诊所。迫切需要改进对人类乳腺癌的药物反应预测测试临床前环境，以确定最佳候选药物。基于我们实验室获得的新见解，作为关键的第一步，我们建议纠正小鼠的内分泌环境，以更充分地模拟内分泌乳腺癌患者的环境。来自两个合作实验室的新颖和独立的见解表明，催乳素作为一种乳腺癌药物敏感性调节因子。催乳素受体的表达，通常是在升高水平，在大多数人类乳腺癌中。然而，目前的鼠标模型是不够的，因为鼠标催乳素可阻止人催乳素受体的激活。因此，目前对药物进行的预测性测试人乳腺癌是在不含催乳素的情况下选择生长的人乳腺癌株进行的。条件。我们现在将测试催乳素作为乳腺癌药物敏感性和生物学调节因子的作用。在这项研究中，表达人催乳素生理水平的小鼠模型是遗传的设计用于对人类乳腺癌异种移植的药物进行更准确的预测性测试。中心假设是PRL受体信号，通过其对乳腺细胞的生存，生长，和分化，调节乳腺癌细胞对抗肿瘤药物的敏感性。与此一致的是，我们进一步假设，在小鼠中，内源性小鼠催乳素已经被生理的人催乳素水平，将恢复人乳腺癌异种移植的催乳素受体信号，并提供更相关的内分泌环境，以改善对乳房临床反应的预测癌症到治疗剂。最后，我们假设表达hPRL的小鼠将允许我们建立新的可移植的乳腺癌株，与人类的原发性乳腺癌更相似，而不是现有的转移性肿瘤细胞系。如果成功，新的小鼠模型将可用于测试大量的人类乳腺癌候选药物，有可能更可靠地预测临床疗效。此外，还成功地含有上皮和间质成分的原发乳腺癌组织移植将为乳腺癌患者个体化治疗的新途径。项目叙事大多数药物在老鼠身上测试人类乳腺癌时，都无法治愈人类的乳腺癌。那里非常需要提高预测候选乳腺癌药物是否对患者有效的能力。至为此，我们开发了一种新的小鼠模型，其荷尔蒙环境更接近于对乳腺癌患者的影响。我们将检验这样一种假设，即新鼠标代表了一种改进的临床前模型，用于更准确地预测乳腺癌候选药物的测试。