Mechanisms Determining Stromal Pten Suppression of Mammary Tumorigenesis

我们发现在乳腺间质成纤维细胞中Pten具有重要的肿瘤抑制功能 肿瘤进展。Pten/Ets2通路中断对MMTV-ErbB2间质成纤维细胞的影响 乳腺肿瘤模型包括EGM及其成分的大量重塑，炎症增加 并增加血管生成。重要的是，可以在人类肿瘤间质中发现Pten中断信号 并且可以预测病人的结果。在与Project 3的合作中，我们最近发现Pten 与非管腔乳腺癌和不良乳腺癌相关的乳腺肿瘤间质亚类中特征丰富 病人结局。 基于这些发现，我们的总体假设是定义肿瘤微环境(TME)途径 间质成纤维细胞中Pten丢失激活将揭示乳腺肿瘤协同进化的机制 以及间质，这些发现可以直接转化为人类乳腺癌。这项建议有三个目的： 目的1：确定肿瘤微环境中Pten调控的基因表达网络。 有待检验的具体假设：间质Pten丢失对ErbB2模型的差异效应是由于 激活与ErbB2功能互补的特定途径(S)。 预期结果：控制TME和TME中不同小区间串扰的网络 与患者预后相关的因素将被确定。 目的2：确定间质Pten通路促进肿瘤进展的机制。 有待检验的特定假设：MIR-320是一种Pten效应器，控制上皮细胞迁移和 肿瘤的生长以及内皮细胞的迁移和/或增殖，将肿瘤侵袭性和血管生成结合在一起。 预期结果：我们将通过实验验证TME中的关键Pten通路，并发现 涉及的机制。 目的3：使用实验验证的依赖Pten的TME网络来识别潜在的生物标记物 用于预测人类乳腺癌的结果和选择治疗策略。 有待检验的特定假设：多种肿瘤微环境细胞中存在间质生物标记物 分区将有助于乳腺癌患者的分层和预测患者的预后。 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，并开始测试它们作为乳腺癌亚类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.