Genetic Modifiers of Intitiation and Progression of Mammary Cancer

到目前为止，这个项目已经为我们转移性乳腺癌的知识做出了许多贡献。首先，它证明了肿瘤细胞的传播具有重要的遗传成分，与转移是由纯粹的体细胞进化过程引起的传统理论相反。第二，第一个转移易感基因Sipa 1在小鼠模型中被鉴定，随后被证明与人类群体的进展有关。第三，发现了一些额外的基因，也有助于人类转移易感性。这些基因的遗传分析揭示了至少两种不同的转移扩散机制的存在。 过去一年的工作继续在此基础上开展。利用我们实验室开创的遗传转移易感性作图策略，我们有助于分析肿瘤进展中的环境因素，重点是膳食脂肪摄入。这些研究表明，与先前的提示性人群研究一致，高脂肪西方饮食促进转移性传播。这些作用由肿瘤自主和非自主因素介导。此外，我们还对其他研究做出了贡献，这些研究检查了与转移扩散和化疗反应相关的表达模式和特征。此外，我们与NCI的许多其他实验室合作，协助开发了一种新的策略，用于将弥散性单个肿瘤细胞转化为增殖性病变的成像。这项新技术准确地复制了对化疗的反应，因此可能为转移性疾病的离体建模提供重要工具。我们实验室的主要工作仍然集中在基因发现和表征。最近，这导致了最重要的转移易感基因之一Brd 4的结构-功能分析的发表。出乎意料的是，一个定义不清的羧基末端结构域被发现介导上皮细胞向间充质细胞的转化和各种干细胞性状的获得。这些数据表明，Brd 4可能在维持肿瘤细胞的分化状态中发挥关键作用。目前正在进一步努力，以进一步确定这一领域的特征。 目前的努力包括正在编写的另外五份手稿。这些努力包括鉴定两个新的转移易感基因，转移相关的microRNA和转移性疾病的转录网络的系统生物学分析。这些努力的详情将在以后的年度报告中介绍。

To date this project has made a number of contributions to our knowledge of metastatic breast cancer. First, it demonstrated that the dissemination of tumor cells has a significant inherited component, contrary to the conventional theory that metastasis resulted from a purely somatic evolutionary process. Second, the first metastasis susceptibility gene, Sipa1, was identified in mouse models and was subsequently demonstrated to be associated with progression in human populations as well. Third, a number of additional genes were discovered that also contribute to human metastatic susceptibility. Genetic analysis of these genes has revealed the presence of at least two different mechanisms for metastatic spread. Work over the past year has continued to build on this basis. Utilizing the genetic metastasis susceptibility mapping strategy pioneered in our laboratory we have contributed to the analysis of environmental factors in tumor progression, focusing on dietary fat intake. These studies have demonstrated, consistent with previous suggestive human population studies, that high-fat western diets promote metastatic dissemination. These effects are mediated by both tumor autonomous and non-autonomous factors. In addition, we have contributed to additional studies examining the expression patterns and signatures associated with metastatic spread and response to chemotherapy. Furthermore, in collaboration with a number of other laboratories at NCI, we assisted in the developing a novel strategy for imaging conversion of disseminated single tumor cells to proliferating lesions. This new technology accurately replicates response to chemotherapy and therefore may provide an important tool for the ex vivo modeling of metastatic disease. Primary efforts of our laboratory continue to be focused on gene discovery and characterization. Most recently this resulted in the publication of a structure-function analysis of one of the most significant metastasis susceptibility genes, Brd4. Unexpectedly, a poorly defined carboxy-terminal domain was found to mediate epithelial-to-mesenchymal transition and acquisition of a variety of stem cell traits. This data suggests that Brd4 may play a pivotal role in maintenance of a differentiated state in tumor cells. Further efforts are currently in progress to further characterize this domain. Current efforts include five additional manuscripts that are in preparation. These efforts include the identification of two novel metastasis susceptibility genes, a metastasis associated microRNA and a systems biology analysis of the transcriptional networks underlying metastatic disease. Details of these efforts will be presented in subsequent annual reports.