Therapeutic Targeting of Breast Cancer Tumor Initiating Cells

描述（由申请人提供）：尽管最近乳腺癌患者的死亡率有所改善，但仍不清楚为什么许多患者在最初接受常规内分泌和/或化疗后复发。我们利用基因工程小鼠模型和临床病人来解决这个问题。使用一个独特的可移植p53无乳腺肿瘤模型，我们已经确定了一个高度富集的肿瘤启动细胞（TIC）亚群。体外和体内实验表明，与大部分肿瘤细胞相比，这些tic中存在更有效的DNA损伤修复机制。在平行研究中，从乳腺癌患者分离的tic中发现了上皮-间充质转化（EMT）相关的基因特征。这种特征存在于以“低claudin”为特征的人类乳腺癌亚群中，最重要的是，在激素和化疗均失败的患者中，这种特征显著增强。通常，tic代表肿瘤内的一小部分细胞，但小鼠和人类的“低claudio”肿瘤似乎高度富集tic。tic可能在本质上更能抵抗放疗和化疗引起的DNA损伤，从而部分解释了它们对常规治疗的抵抗力；它们也被认为是转移性传播、肿瘤休眠和复发的原因。因此，为了帮助阐明导致tic固有治疗耐药的机制和信号通路，并开发能够克服这种对常规治疗耐药的治疗方法，我们提出了以下具体目标：包括claudin- low/spindloid类在内的小鼠p53阴性肿瘤不同亚型的tic分析。目标2。确定在p53无cladin -low/纺锤样肿瘤中EMT通路的扰动是否会改变其表型特性。目标3。目的：确定tic的治疗敏感性。有效靶向乳腺癌肿瘤起始细胞的一个迫切需要是开发改进的临床前模型来测试这些疗法。为了满足这一需求，我们已经确定了发展低claudin /spindloid肿瘤的小鼠模型，其中大部分肿瘤细胞似乎是tic。因此，我们相信我们有一个合适的和有效的模型来研究重要的信号通路和治疗方法。这项多项目资助将Rosen实验室的干细胞和信号通路专业知识与Perou实验室的基因组学，生物信息学和治疗学专业知识结合起来，因此代表了两者之间的良好协同作用。

DESCRIPTION (provided by applicant): Despite recent improvements in mortality for breast cancer patients, it is still not known why many patients relapse even after an initial response to conventional endocrine and/or chemotherapies. We have approached this question using both genetically engineered mouse models and in patients in the clinic. Using a unique transplantable p53 null mammary tumor model we have identified a highly enriched Tumor-Initiating Cell (TIC) subpopulation. Both in vitro and in vivo experiments indicate that more efficient DNA damage repair mechanisms exist in these TICs as compared to the bulk of the tumor cells. In parallel studies, an epithelial- mesenchymal transition(EMT)-related gene signature was identified in TICs isolated from breast cancer patients. This signature was present in the subset of human breast cancers characterized as "claudin-low", and most importantly was significantly enriched in patients who failed both hormonal and chemotherapy. Often TICs represent a small subpopulation of cells within a tumor, but "claudin-low" tumors of both mice and humans appear to be highly enriched in TICs. TICs may be intrinsically more resistant to DNA damage induced by radiation and chemotherapy treatments, thus in part explaining their resistance to conventional treatments; they have also been suggested to be responsible for metastatic dissemination, tumor dormancy and recurrence. Thus, to help elucidate the mechanisms and signaling pathways that are responsible for the intrinsic therapeutic resistance of TICs, and to develop therapies that can overcome this resistance to conventional treatments, the following Specific Aims are proposed: Aim 1. Analysis of TICs in the different subtypes of the murine p53 null tumors including the claudin- low/spindloid class. Aim 2. To determine if perturbation of EMT pathways in the p53 null claudin-low/spindloid tumors alters their phenotypic properties. Aim 3. To determine the therapeutic sensitivity of TICs. One pressing need to effectively target breast cancer tumor initiating cells is the development of improved preclinical models to test these therapies. To address this need, we have identified mouse models that develop claudin-low/spindloid tumors, where the bulk of the tumors cells appear to be TICs. Thus, we believe that we have an appropriate and validated model for the investigation of important signaling pathways and therapeutics. This multiPI grant combines the considerable stem cell and signaling pathway expertise in the Rosen laboratory with the genomics, bioinformatics and therapeutics expertise in the Perou laboratory and, therefore represents an excellent synergy between the two. )