Experimental Modeling of Human Breast Cancer in Mice

人类乳腺癌小鼠实验模型

• 批准号: 8212336
• 负责人: HALLGEIR RUI
• 金额: $ 31.34万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-07 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212336
• 关键词: Adjuvant; Antibodies; Antineoplastic Agents; Apoptotic; 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; public health relevance; receptor; response; therapeutic target; tumor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：尽管学术界、政府和制药机构付出了巨大的开支和努力，但大多数在小鼠临床前试验中显示出对人类乳腺癌有希望的药物在临床上未能治愈乳腺癌。非常需要在临床前环境中改进人类乳腺癌的药物反应预测测试，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，我们建议纠正小鼠内分泌环境，以更充分地模拟乳腺癌患者的内分泌环境。来自两个合作实验室的新颖和独立的见解表明，催乳素作为人类乳腺癌药物敏感性的调节剂。催乳素受体在大多数人乳腺癌中表达，通常水平升高。然而，目前的小鼠模型是不够的，因为小鼠催乳素阻止人类催乳素受体的激活。因此，目前针对人乳腺癌的药物的预测性测试是在选择用于在无催乳素条件下生长的人乳腺癌细胞系上进行的。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剂的作用。对于这项研究，表达生理水平的人类催乳素的小鼠模型已经被基因工程改造，用于对人类乳腺癌异种移植物进行更准确的药物预测测试。中心假设是PRL受体信号传导通过其对乳腺细胞存活、生长和分化的影响调节乳腺癌细胞对抗肿瘤剂的敏感性。与此一致，我们进一步假设，小鼠，其中内源性小鼠催乳素已被替换为生理水平的人催乳素，将恢复催乳素受体信号在人乳腺癌异种移植，并提供一个更相关的内分泌环境，改善乳腺癌的临床反应性预测治疗药物。最后，我们假设hPRL表达小鼠将使我们能够建立新的和可移植的乳腺癌细胞系，这些细胞系比现有的转移源性肿瘤细胞系更类似于原发性乳腺癌。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，并有可能更可靠地预测临床疗效。此外，成功移植具有上皮和基质成分的原发性乳腺癌组织将为治疗乳腺癌患者的新的个性化医学方法铺平道路。 公共卫生相关性：大多数药物在小鼠中对人类乳腺癌进行测试时，未能治愈人类乳腺癌。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。为此，我们开发了一种新的小鼠模型，其激素环境与乳腺癌患者的激素环境更相似。我们将测试一个假设，即新的小鼠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。

项目成果

Cyclin D3 compensates for the loss of cyclin D1 during ErbB2-induced mammary tumor initiation and progression.

细胞周期蛋白 D3 可以补偿 ErbB2 诱导的乳腺肿瘤发生和进展过程中细胞周期蛋白 D1 的损失。

• DOI: 10.1158/0008-5472.can-11-1783
• 发表时间: 2011
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Zhang,Qian;Sakamoto,Kazuhito;Liu,Chengbao;Triplett,AleataA;Lin,Wan-chi;Rui,Hallgeir;Wagner,Kay-Uwe
• 通讯作者: Wagner,Kay-Uwe