Inflammation in Breast Cancer Initiation and Promotion

乳腺癌发生和促进过程中的炎症

• 批准号: 8444711
• 负责人: Kathryn L Schwertfeger
• 金额: $ 29.45万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444711
• 关键词: A Mouse; AP20187; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Breast Cancer Cell; Breast Carcinoma; Cancer Patient; Cell Communication; Cells; Cleaved cell; Data; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease Progression; Early treatment; Elements; Epiregulin; Epithelial; Epithelial Cells; ErbB4 gene; Event; FGFR1 gene; Fibroblast Growth Factor Receptor 1; Gene Expression; Goals; Health; Human; Hyperplasia; Immune; In Vitro; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukins; Laboratories; Lead; Lesion; Link; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Membrane; Methods; Modeling; Molecular; Neoplasm Metastasis; Oncogenes; Pathway interactions; Patients; Peptide Hydrolases; Phenotype; Play; Process; Proteolysis; Recruitment Activity; Research; Role; STAT5A gene; Signal Pathway; Staging; Stromal Cells; Surface; Testing; Transgenic Mice; Tumor Cell Invasion; Tumor stage; Up-Regulation; angiogenesis; cancer initiation; cancer type; cytokine; design; extracellular; high risk; in vivo; in vivo Model; macrophage; malignant breast neoplasm; mammary epithelium; mouse model; novel; novel marker; novel therapeutics; outcome forecast; response; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Inflammation within the tumor microenvironment correlates with increased invasiveness and poor prognosis in many types of cancer, including breast cancer. Immune cells promote breast cancer cell invasion both in vitro and in vivo, implicating these tumor-stromal cell interactions in metastatic disease progression. Specifically, the presence of macrophages in breast carcinomas has been linked to angiogenesis, metastasis and poor prognosis. At present, however, little is known about how macrophages and inflammatory processes contribute to breast cancer initiation. Studies using a novel mouse model of mammary tumorigenesis have demonstrated that activation of the fibroblast growth factor receptor 1 (FGFR1) oncogene results in a dramatic inflammatory response within the mammary gland. Specifically, macrophages have been shown to play a causal role in the formation of FGFR1-mediated preneoplastic lesions in the mammary gland. The use of both in vitro and in vivo models has led to the identification of inflammatory mediators that contribute to pro-tumorigenic epithelial cell/macrophage interactions. These studies have led to the hypothesis that FGFR1 induces expression of the inflammatory cytokine interleukin-1 beta (IL-1¿), leading to a cascade of events involving induction of the protease Adam17 and shedding of epiregulin, which then acts on the macrophages to induce a tumor associated macrophage phenotype. The following specific aims are proposed: 1) Define the mechanisms that regulate epithelial cell induction and shedding of Ereg, a novel downstream target of mammary tumor-associated inflammation. 2) Evaluate the ability of mammary epithelial cell-derived Ereg to regulate macrophage activity using in vitro and in vivo models. 3) Determine the importance of the ErbB4/Stat5 signaling pathway in stimulating the tumor associated macrophage phenotype. The significance of these studies is that they will further define macrophage function during early stages of tumor formation, leading to the identification of novel markers that can be used in both diagnosis and treatment of early-stage breast tumors. In the longer term, patients at high risk for breast cancer may benefit from specific anti-inflammatory therapies that could be used to inhibit tumor formation and progression.

描述（由申请人提供）：在许多类型的癌症中，肿瘤微环境中的炎症与侵袭性增加和预后不良相关，包括乳腺癌。免疫细胞促进乳腺癌细胞在体内和体外的侵袭，暗示这些肿瘤-基质细胞相互作用在转移性疾病进展中。具体来说，巨噬细胞在乳腺癌中的存在与血管生成、转移和预后不良有关。然而，目前对巨噬细胞和炎症过程如何促进乳腺癌的发生知之甚少。使用一种新的乳腺肿瘤发生小鼠模型的研究表明，成纤维细胞生长因子受体1 （FGFR1）癌基因的激活会导致乳腺内剧烈的炎症反应。具体而言，巨噬细胞已被证明在乳腺中fgfr1介导的肿瘤前病变的形成中起因果作用。体外和体内模型的使用已经确定了促进致瘤性上皮细胞/巨噬细胞相互作用的炎症介质。这些研究提出了这样的假设：FGFR1诱导炎症细胞因子白细胞介素-1 β (IL-1)的表达，导致一系列事件，包括蛋白酶Adam17的诱导和表调节蛋白的脱落，然后表调节蛋白作用于巨噬细胞，诱导肿瘤相关的巨噬细胞表型。提出以下具体目标：1)明确调节上皮细胞诱导和Ereg脱落的机制，Ereg是乳腺肿瘤相关炎症的新下游靶点。2)通过体外和体内模型评估乳腺上皮细胞来源的Ereg调节巨噬细胞活性的能力。3)确定ErbB4/Stat5信号通路在刺激肿瘤相关巨噬细胞表型中的重要性。这些研究的意义在于，它们将进一步明确巨噬细胞在肿瘤形成早期的功能，从而发现新的标志物，可用于早期乳腺肿瘤的诊断和治疗。从长远来看，乳腺癌高风险患者可能受益于可用于抑制肿瘤形成和进展的特定抗炎疗法。