Mechanisms Determining Stromal Pten Suppression of IVIammary Tumorigenesis

基质 Pten 抑制 IVI 乳房肿瘤发生的机制

• 批准号: 8246040
• 负责人: Michael C. Ostrowski
• 金额: $ 30.11万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246040
• 关键词: Affect; Binding; Biological Assay; Biological Markers; Breast Cancer Model; Cancer Etiology; Cancer Patient; Cell Communication; Cells; Cessation of life; ChIP-seq; Collaborations; Coupling; Data; Endothelial Cells; Epigenetic Process; Epithelial Cells; Evolution; Extracellular Matrix; Fibroblasts; Figs - dietary; Gene Expression; Gene Expression Profile; Growth; Hand; Human; In Vitro; Individual; Inflammation; Knowledge; Mammary Neoplasms; Mass Spectrum Analysis; Messenger RNA; Methods; MicroRNAs; Modeling; Molecular; Molecular Profiling; Mouse Mammary Tumor Virus; Mus; Outcome; Pathway interactions; Patients; Phenotype; Proteome; Role; Technology; Testing; Translating; Tumor Suppressor Proteins; Woman; angiogenesis; base; cell growth; cell motility; complement pathway; genetic analysis; genome-wide; in vivo; laser capture microdissection; macrophage; malignant breast neoplasm; migration; mouse model; neoplastic cell; novel strategies; programs; tool; transcription factor; treatment strategy; tumor; tumor progression; tumorigenesis

We have discovered a critical tumor suppressor function for Pten in stromal fibroblasts during mammary tumor progression. Consequences of Pten/Ets2 pathway disruption in stromal fibroblasts in the MMTV-ErbB2 mammary tumor model include massive remodeling of the EGM and its constituents, increased inflammation and increased angiogenesis. Importantly, the Pten disruption signature can be found in human tumor stroma and can predict patient outcome. In collaboration with Project 3, we have recently found that the Pten signature is enriched in breast tumor stromal subclasses associated with non-luminal breast cancer and poor patient outcome. Based on these findings, our overall hypothesis is that defining the tumor microenvironment (TME) pathways activated by Pten loss in stromal fibroblasts will uncover the mechanisms of co-evolution of mammary tumor and stroma, findings that can be translated directly to human breast cancer. The proposal has three Aims: AIM 1: Identify gene expression networks regulated by Pten in the tumor microenvironment. Specific hypothesis to be tested: The differential effect of stromal Pten loss on the ErbB2 model is due to the activation of a specific pathway(s) that complements ErbB2 function. Expected Outcome: Networks that control cross-talk between different cell compartments in the TME and that correlate with patient outcome will be identified. AIM 2: Determine mechanisms by which stromal Pten pathways contribute to tumor progression. Specific Hypothesis to be tested: miR-320 is one Pten effector that controls epithelial cell migration and growth, as well as endothelial migration and/or proliferation, coupling tumor invasiveness and angiogenesis. Expected Outcome: We will experimentally verify the critical Pten pathways in the TME, and uncover the mechanisms involved. Aim 3: Use experimentally verified Pten-dependent TME networks to identify potential biomarkers for predicting outcome and selecting treatment strategies for human breast cancer. Specific Hypothesis to be tested: Stromal biomarkers present in multiple tumor microenvironment cell compartments will be useful in stratifying breast cancer patients and predicting patient outcome. Expected Outcome: We will reveal the pathways in the mouse models that are most relevant to human breast cancer, and begin testing their role as potential biomarkers for breast cancer subclasses.

我们在乳腺成纤维细胞中发现了PTEN的关键肿瘤抑制功能 肿瘤进展。 MMTV-ERBB2中基质成纤维细胞中PTEN/ETS2途径破坏的后果 乳腺肿瘤模型包括对EGM及其成分的大规模重塑，炎症增加 并增加了血管生成。重要的是，可以在人类肿瘤基质中找到PTEN破坏特征 并可以预测患者的结果。与项目3合作，我们最近发现PTEN 签名富含与非腹腔乳腺癌相关的乳腺肿瘤基质亚类 病人的结果。 基于这些发现，我们的总体假设是定义肿瘤微环境（TME）途径 通过基质成纤维细胞中的PTEN损失激活，将发现乳腺肿瘤共同进化的机制 和基质，可以直接转化为人类乳腺癌的发现。该提案有三个目标： 目标1：确定肿瘤微环境中PTEN调控的基因表达网络。 要测试的具体假设：基质PTEN损失对ERBB2模型的差异效应是由于 补充ERBB2功能的特定途径的激活。 预期结果：控制TME和 将确定与患者结局相关的。 目标2：确定基质PTEN途径有助于肿瘤进展的机制。 要测试的具体假设：miR-320是控制上皮细胞迁移和 生长以及内皮迁移和/或增殖，耦合肿瘤的侵袭性和血管生成。 预期结果：我们将通过实验验证TME中的关键PTEN途径，并发现 涉及的机制。 目标3：使用实验验证的PTEN依赖性TME网络识别潜在的生物标志物 预测结果并选择人类乳腺癌的治疗策略。 要测试的特定假设：多个肿瘤微环境细胞中存在的基质生物标志物 隔室将有助于分层乳腺癌患者并预测患者的预后。 预期结果：我们将揭示与人类最相关的鼠标模型中的途径 乳腺癌，并开始测试其作为乳腺癌亚类潜在生物标志物的作用。