Mechanisms of Metastasis and Evasion of TGF-Beta Tumor Suppression Breast Cancer

骨和肺是乳腺癌转移复发的两个最常见部位。在工作支持 通过这项授权，我们从乳腺癌细胞系中选择了器官特异性转移细胞亚群， MDA-MB-231，并推导出骨转移基因表达特征（BoMS）和肺转移基因表达特征（BoMS）。 签名（LMS）。我们在功能上验证了这些基因中的许多作为骨或肺转移的介质。 与W. Gerald和A. Olshen，我们显示了这些特征预测队列中复发部位的能力 原发性乳腺肿瘤我们正在定义这些基因的功能，包括 骨代谢相关基因IL 11和OPN在溶骨转移过程中破骨细胞活化中的作用及LMS基因的作用 表皮调节素、COX 2、MMP 1和MMP 2与肿瘤新生血管和转移性外渗与R. Benezra和H. Varmus，我们正在定义LMS基因ID 1在赋予肿瘤起始能力中的作用， 基底亚型的转移性乳腺癌。基于这些见解，我们提出了与L。诺顿 关于某些转移性功能如何可能是大肿瘤与恶性肿瘤之间的关联的“肿瘤自我播种”假说， 肿瘤大小、快速生长速度和转移行为在临床癌症中常见。此外，我们还有 明确的机制，使乳腺癌细胞避免TGFR的肿瘤抑制作用。使用 在P01-CA 94060下开发的小鼠模型中，我们证明了TGFIJ-Smad通路在 乳腺癌转移到肺和骨。这些模型和靶基因提供了相关的检测系统 以测试现有的和新的药物对乳腺癌转移的有效性。在此基础上 进展，在下一个资助期，我们计划使用 来自新鲜胸腔积液的原发性恶性细胞（Aim 1）。我们将努力定义功能和 经验证的转移基因之间的治疗相关相互作用（目的2）。我们将通过临床鉴定 介导TGFB在肺和骨中的促转移作用的相关基因（目的3）。此外，我们将 实验测试“肿瘤自我播种”假设（目标4）。这些具体目标中的每一个都是 开发和应用相关的分析系统，以测试治疗剂的有效性 在项目计划中学习。总之，我们建议继续乳腺癌的发现步伐， 癌症转移，这是在以前的资助期间发起的合作研究工作。

Bone and lung are the two most frequent sites of metastatic recurrence in breast cancer. In work supported by this grant we selected organ-specific metastasis cell subpopulations from the breast carcinoma cell line MDA-MB-231, and derived a bone metastasis gene expression signature (BoMS) and a lung metastasis signature (LMS). We functionally validated many of these genes as mediators of bone or lung metastasis. With W. Gerald and A. Olshen, we showed the ability of these signatures to predict site of relapse in cohorts of primary breast tumors. We are defining the functions that are fulfilled by these genes, including roles of BoMS genes IL11 and OPN in osteoclast activation during osteolytic metastasis, and roles of LMS genes Epiregulin, COX2, MMP1 and MMP2 in tumor neovascularization and metastatic extravasation. With R. Benezra and H. Varmus we are defining the role of LMS gene ID1 in conferring tumor-initiating capacity to metastatic breast cancers of the basal subtype. Based on these insights, we have proposed with L. Norton the "tumor self-seeding" hypothesis of how certain metastatic functions may underlie the association of large tumor size, rapid growth rate, and metastatic behavior often seen in clinical cancer. Additionally, we have defined mechanisms that allow breast cancer cells to avert the tumor-suppressive action of TGFR. Using mouse models developed under P01-CA94060, we demonstrated roles of the TGFIJ-Smad pathway in breast cancer metastasis to lung and bone. These models and target genes provide relevant assay systems to test the effectiveness of existing and novel drugs against breast cancer metastasis. Building on this progress, in the next grant period we are planning to identify new bone and lung metastasis genes using primary malignant cells from fresh pleural effusions (Aim 1). We will seek to define functional and therapeutically relevant interactions between validated metastasis genes (Aim 2). We will identify clinically relevant genes mediating the pro-metastatic action of TGFB in lung and bone (Aim 3). Furthermore, we will experimentally test the "tumor self-seeding" hypothesis (Aim 4). Built into each of these specific aims is the development and application of relevant assay systems to test the effectiveness of therapeutic agents under study in the Program Project. In sum, we are proposing to continue on the pace of discovery in breast cancer metastasis that was initiated during the previous grant period by this cooperative research effort.