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

调节三阴性乳腺癌基础表型和转移表型的途径

• 批准号: 9246896
• 负责人: Teresa L Wood
• 金额: $ 53.17万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9246896
• 关键词: Basal Cell; Biological Markers; Breast Cancer Cell; Breast Epithelial Cells; Cancer Biology; Cells; Classification; Data; ERBB2 gene; Epithelial; Epithelial Cells; Gene Mutation; Goals; Human; Inflammatory; Insulin Receptor; Insulin-Like Growth Factor Receptor; Insulin-Like-Growth Factor I Receptor; Knowledge; Mammary Neoplasms; Mammary gland; Mediating; Metastatic to; Modeling; Molecular Profiling; Mouse Mammary Tumor Virus; Mus; Myoepithelial; Neoplasm Metastasis; Pathway interactions; Patients; Pattern; Phenotype; Primary Neoplasm; Protein Tyrosine Kinase; Publishing; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Research; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tumor Initiators; cancer subtypes; cytokine; experimental study; insight; malignant breast neoplasm; molecular marker; mouse model; notch protein; progenitor; receptor; self-renewal; triple-negative invasive breast carcinoma; tumor; tumor heterogeneity; tumor initiation; tumor microenvironment; tumorigenesis

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.

概括 三阴性乳腺癌 (TNBC) 占乳腺肿瘤的 10-20%； 75%的 它们具有类似基底的表型。然而，基础表型本身并不 必然预测转移表型。因此，制定明确的 了解控制肿瘤表型的途径和分子 有效治疗乳腺癌患者并识别侵袭性、 转移性肿瘤概况。这项研究的长期目标是了解什么 调节 TNBC 的基础和转移表型。我们已经鉴定出酪氨酸 激酶信号通路被破坏时会增强小鼠的基础表型 TNBC 模型并将肿瘤从非转移性转变为转移性。我们发表的 数据和新的初步数据支持该模型在子类型中的相关性 人类 TNBC 并为我们的假设提供了基础，即腔内和基底 谱系在 TNBC 的表型中具有不同的功能。拟议的目标 研究的目的是定义细胞机制和其他信号通路的改变 负责肿瘤表型的这些重要变化。三个具体目标是 提议证明 1) 管腔胰岛素样生长因子受体 (IGF-1R) 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-1R 调节转移表型，3) IGF-1R 的表达 在具有高 Wnt 和 EMT 特征的人类 TNBC 中，该值降低。完成时 为了实现这些目标，我们期望获得关于如何相互作用的关键信息 酪氨酸激酶、自我更新和炎症途径调节 TNBC 的表型。