MCF10DCIS.com as a preclinical chemopreventive screen

我们的目标是验证临床前异种移植模型，以评估化学制剂改变乳腺癌原位癌替代终点生物标记物(SEB)表达的能力。我们已经开发出一种人乳腺上皮细胞系MCF10DCIS.com，它能产生粉刺样型的导管原位癌。在免疫缺陷小鼠体内注射Matrigel中的1x10/7细胞6-8周后，获得了近1克的组织。我们将能够通过与卡马诺斯癌症研究所正在进行的一项临床研究的结果直接比较来验证该模型的结果，在该研究中，被诊断为DCIS的患者在手术前三周每天服用100毫克大豆异黄酮类药物。分析手术标本中连接蛋白43、p21、bax、bcl2、p21和CDK5的表达。然而，临床前模型允许我们用化学预防药物治疗一组异种移植小鼠，并以多个时间间隔而不是临床研究中可能的单个时间点来确定治疗和未治疗的皮损中生物标记物的表达。我们还将能够测试其他化学预防药物、剂量和组合。异种移植损伤的大小将使我们能够研究化学预防药物、剂量和组合。异种移植病变的大小将使我们能够查看治疗前和治疗后的许多额外的生物标志物，而不是临床标本中可能获得的稀疏材料。一旦得到验证，MCF10DCIS.com将提供一种独特的人原位导管癌异种移植模型，用于快速筛选可能的化学预防药物。与MCF10AT1原位联合用于快速筛选可能的化学预防药物。与进行性乳腺癌前疾病的MCF10AT1异种移植模型相结合，该模型还将提供一种验证不同SEB在筛选化学预防药物方面的相关性的方法。

Our objective is to validate a preclinical xenograft model for assessment of the ability of chemical agents to alter surrogate end- point biomarker (SEB) expression in breast carcinoma in situ. We have developed a human breast epithelial cell line, MCF10DCIS.com, which produces ductal carcinoma in situ of the comedo type. Nearly one gram of tissue is obtained 6-8 weeks after injecting 1x10/7 cells in Matrigel into immune deficient mice. We will be able to validate results with the model by direct comparison with results of a clinical study being conducted at the Karmanos Cancer Institute in which patients diagnosed with DCIS are given 100 mg of soy isoflavones daily for three weeks prior to surgery. Surgical specimens are analyzed for expression of a number of markers including connexin 43, p21, bax, bcl-2, p21, and CDK5. However, the preclinical model allows us to treat groups of xenografted mice with chemopreventive agents and determine expression of biomarkers in lesions from treated and untreated at multiple intervals rather than the single time point possible in the clinical study. We will also be able to test additional chemopreventive agents, doses, and combinations. The size of the xenograft lesions will allow us to look at chemopreventive agents, doses, and combinations. The size of the xenograft lesions will allow us to look at many additional biomarkers, both before and after treatment, than the sparse material likely to be available from the clinical specimens. Once validated, MCF10DCIS.com will provide a unique xenograft model of human ductal carcinoma in situ for rapid screening of putative chemopreventive agents. In combination with the MCF10AT1 in situ for rapid screening of putative chemopreventive agents. In combination with the MCF10AT1 xenograft model of progressive premalignant breast disease, the model will also provide a means of validating the relevance of different SEBs for screening chemopreventive agents.