Pathways that regulate basal and metastatic phenotypes in triple negative breast cancers

摘要 三重阴性乳腺癌(TNBCs)占乳腺癌的10%-20%；75% 这些细胞的表型呈基底型。然而，基本表型本身并不 必然预示着转移性表型。因此，制定一项明确的 对控制肿瘤表型的途径和分子的了解 有效治疗乳腺癌患者并确定侵袭性、 转移性肿瘤概况。这项研究的长期目标是了解 调节TNBC的基础表型和转移表型。我们已经鉴定出一种酪氨酸 激酶信号通路，当被破坏时，增加小鼠的基本表型 TnBC模型，将肿瘤从非转移转化为转移。我们出版的 数据和新的初步数据支持该模型在一个子类型中的相关性 并为我们的假设提供了基础，即管腔和基底 在TNBCs的表型中，谱系具有明显的功能。建议的目标是 研究的目的是确定细胞机制和其他信号通路的变化 对肿瘤表型的这些重要变化负责。三个具体目标是 提出证明1)腔内胰岛素样生长因子受体(IGF-1R) 调节腔上皮细胞向基底细胞的转化和肿瘤的启动表型，2) 肌上皮细胞IGF-1R调节转移表型，3)IGF-1R的表达 在具有高Wnt和EMT签名的人TNBCs中，IS降低。在完成时 目标，我们希望已经获得了关键信息，在如何相互作用 酪氨酸激酶、自我更新和炎症通路调节TNBC的表型。

Summary Triple negative breast cancers (TNBCs) represent 10-20% of breast tumors; 75% of these have a basal-like phenotype. However, the basal phenotype itself does not necessarily predict a metastatic phenotype. Thus, it is critical to develop a clear understanding of the pathways and molecules that control tumor phenotypes to more effectively treat patients with breast cancer and to identify biomarkers of aggressive, metastatic tumor profiles. The long-term goal of this research is to understand what regulates basal and metastatic phenotypes in TNBC. We have identified a tyrosine kinase signaling pathway that, when disrupted, augments a basal phenotype in a mouse model of TNBC and converts tumors from non-metastatic to metastatic. Our published data and new preliminary data support the relevance of this model in a subtype of human TNBCs and provide the basis for our hypothesis that the luminal and basal lineages have distinct functions in the phenotypes of TNBCs. The goal of the proposed studies is to define the cellular mechanisms and alterations in other signaling pathways responsible for these important changes in tumor phenotypes. Three specific aims are proposed to demonstrate that 1) luminal insulin-like growth factor receptor (IGF-1R) regulates luminal to basal cell conversion and tumor-initiating phenotype, 2) myoepithelial IGF-1R regulates a metastatic phenotype, and 3) expression of the IGF-1R is decreased in human TNBCs with high Wnt and EMT signatures. At the completion of the aims, we expect to have obtained critical information in how interactions between tyrosine kinase, self-renewal and inflammatory pathways regulate phenotypes in TNBC.