GENETIC REQUIREMENTS FOR TUMORIGENIC COVERSION

致瘤性覆盖的遗传要求

• 批准号: 6166313
• 负责人: ROBERT A WEINBERG
• 金额: $ 11.63万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6166313
• 关键词: Retroviridae; athymic mouse; breast neoplasms; cell cell interaction; connective tissue cells; guanine nucleotide binding protein; metastasis; neoplasm /cancer genetics; neoplasm /cancer invasiveness; neoplastic transformation; oncogenes; simian virus 40; telomerase; transfection /expression vector; tumor antigens

DESCRIPTION: (Applicant's Description) The primary goal of this project is to develop an in vitro system for the transformation of normal human mammary epithelial cells (HMECs) into tumor cells with a defined set of genes. The development of such a system would mark the first time that this has been achieved and greatly enhance our understanding of the genetic requirements for transformation of HMECs in several respects. First, the in vitro transformation of HMECs would allow us to define the minimal requirements for the transformation of these cells and define which cellular signaling pathways must be disrupted for tumorigenic conversion. Second, it would enable us link each genetic mutation with a distinct role in the transformation process. Following the creation of this purely genetic system for the transformation of HMECs, we will refine the model to more accurately reflect the development of human breast cancer in two ways. First, we will replace the initial cohort of transforming genes with genes known to be involved in human breast cancer. This will allow us to classify the genes which have been found to be mutated in breast cancer over the past two decades into groups based on their causal role in the transformation process. Second, we will determine the requirements for tumor formation in the mammary stromal environment by injecting the transformed HMECs into the mouse mammary fat pad and assessing their tumorigenic potential. Lastly, we will investigate the genetic requirements for two of the later stages in breast cancer progression, invasion and metastasis. These requirements will be addressed using both a candidate gene approach and a retroviral cDNA expression screen in order to isolate invasion and metastasis-promoting genes.

描述：（申请人的描述） 该项目的主要目标是开发一个体外系统 正常人乳腺上皮细胞（HMEC）转化为肿瘤 具有一组明确基因的细胞。这样一个系统的开发将标志着 这是第一次实现这一目标，极大地提高了我们的 了解 HMEC 转化的遗传要求 几个方面。首先，HMEC 的体外转化将使我们能够 定义这些细胞转化的最低要求和 定义哪些细胞信号传导途径必须被破坏才能致瘤 转换。其次，它将使我们能够将每个基因突变与一个 在转型过程中发挥着独特的作用。 在创建了这个用于转化的纯遗传系统之后 HMEC，我们将完善模型以更准确地反映 人类乳腺癌的发生有两种方式。首先，我们将替换最初的队列 用已知与人类乳腺癌有关的基因转化基因。 这将使我们能够对已发现突变的基因进行分类 过去二十年中乳腺癌根据其因果关系进行分组 转型过程中的作用。其次，我们将确定要求 通过注射在乳腺基质环境中形成肿瘤 将 HMEC 转化到小鼠乳腺脂肪垫中并评估其 致瘤潜力。最后，我们将调查遗传要求 对于乳腺癌进展的两个后期阶段，侵袭和 转移。这些要求将通过使用候选基因来解决 方法和逆转录病毒 cDNA 表达筛选，以隔离入侵 和促进转移的基因。