Mechanisms Determining Stromal Pten Suppression of IVIammary Tumorigenesis

我们已经发现了乳腺癌时间质成纤维细胞中Pten的重要肿瘤抑制功能， 肿瘤进展。MMTV-ErbB 2中基质成纤维细胞中Pten/Ets 2途径破坏的后果 乳腺肿瘤模型包括EGM及其成分的大量重塑，炎症增加 和增加的血管生成。重要的是，Pten破坏特征可以在人类肿瘤基质中发现。 并且可以预测患者的结果。在与项目3的合作中，我们最近发现Pten 信号在与非管腔型乳腺癌相关的乳腺肿瘤基质亚类中富集， 患者结局。 基于这些发现，我们的总体假设是，定义肿瘤微环境（TME）通路 在乳腺间质成纤维细胞中，Pten缺失所激活的p53基因将揭示乳腺肿瘤协同进化的机制 和间质，这些发现可以直接转化为人类乳腺癌。该提案有三个目标： 目的1：鉴定肿瘤微环境中Pten调控的基因表达网络。 待检验的特定假设：基质Pten损失对ErbB 2模型的差异效应是由于 激活补充ErbB 2功能的特定途径。 预期结果：控制TME中不同细胞区室之间串扰的网络， 与患者结局相关的信息。 目的2：确定基质Pten通路促进肿瘤进展的机制。 待检验的特定假设：miR-320是一种Pten效应物，其控制上皮细胞迁移， 生长以及内皮迁移和/或增殖，耦合肿瘤侵袭和血管生成。 预期结果：我们将通过实验验证TME中的关键Pten通路，并揭示TME中的Pten通路。 涉及的机制。 目的3：使用实验验证的Pten依赖性TME网络来识别潜在的生物标志物 用于预测人类乳腺癌的结果和选择治疗策略。 待检验的特定假设：多种肿瘤微环境细胞中存在基质生物标志物 隔室将可用于对乳腺癌患者进行分层并预测患者结果。 预期结果：我们将揭示小鼠模型中与人类最相关的通路。 乳腺癌，并开始测试其作为乳腺癌亚类的潜在生物标志物的作用。

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.