Experimental Modeling of Human Breast Cancer in Mice

描述（由申请人提供）：尽管学术界、政府和制药机构投入了巨大的资金和努力，但大多数在小鼠临床前试验中显示出治疗人类乳腺癌希望的药物，在临床上却无法治愈乳腺癌。在临床前环境中，非常需要改进人类乳腺癌的药物反应预测测试，以确定最佳的候选药物。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类乳腺癌中表达，通常水平升高。然而，目前的小鼠模型是不充分的，因为小鼠催乳素阻止人类催乳素受体的激活。因此，目前针对人类乳腺癌的药物预测测试是在人类乳腺癌细胞系上进行的，这些细胞系是在无催乳素的条件下选择生长的。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。在这项研究中，一种表达人类泌乳素生理水平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药物进行更准确的预测测试。核心假设是PRL受体信号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药物的敏感性。与此一致，我们进一步假设，在小鼠体内，内源性小鼠催乳素被生理水平的人类催乳素所取代，将恢复人类乳腺癌异种移植中催乳素受体的信号，并为更好地预测乳腺癌对治疗药物的临床反应性提供更相关的内分泌环境。最后，我们假设表达hPRL的小鼠将允许我们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接近于原发性乳腺癌。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，具有上皮和基质成分的原发性乳腺癌组织的成功移植将为治疗乳腺癌患者的新的个性化医学方法铺平道路。

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.