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

总结 三阴性乳腺癌（TNBC）占乳腺肿瘤的10-20%;占乳腺癌的75%。 这些具有基底样表型。然而，基础表型本身并不 必然预示转移表型。因此，制定一个明确的 了解控制肿瘤表型的途径和分子， 有效地治疗乳腺癌患者并鉴定侵袭性， 转移性肿瘤特征。这项研究的长期目标是了解 调节TNBC中的基础和转移表型。我们发现了一种酪氨酸 激酶信号通路，当被破坏时，其增强小鼠中的基础表型 TNBC模型，并将肿瘤从非转移性转化为转移性。我们的出版 数据和新的初步数据支持这一模型的相关性， 并为我们的假设提供了基础，即管腔和基底 谱系在TNBC的表型中具有不同的功能。建议的目标 研究的目的是确定其他信号通路的细胞机制和改变 负责肿瘤表型的这些重要变化。三个具体目标是 提出证明1）管腔胰岛素样生长因子受体（IGF-1 R） 调节管腔细胞向基底细胞的转化和肿瘤起始表型，2） 肌上皮IGF-1 R调节转移表型，和3）IGF-1 R的表达 在具有高Wnt和EMT特征的人TNBC中降低。完成时 的目标，我们希望获得关键信息，如何相互作用之间 酪氨酸激酶、自我更新和炎症途径调节TNBC中的表型。

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.