Inflammation in Breast Cancer Initiation and Promotion

描述（由申请人提供）：肿瘤微环境内的炎症与许多类型癌症（包括乳腺癌）的侵袭性增加和预后不良相关。 免疫细胞促进乳腺癌细胞在体外和体内的侵袭，暗示这些肿瘤间质细胞的相互作用在转移性疾病的进展。 具体而言，乳腺癌中巨噬细胞的存在与血管生成、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。 使用新型小鼠乳腺肿瘤发生模型的研究表明，成纤维细胞生长因子受体1（FGFR 1）癌基因的激活导致乳腺内显著的炎症反应。 具体而言，巨噬细胞已被证明在乳腺中FGFR 1介导的癌前病变的形成中发挥因果作用。体外和体内模型的使用已经导致了有助于促肿瘤发生上皮细胞/巨噬细胞相互作用的炎症介质的鉴定。 这些研究导致了这样的假设，即FGFR 1诱导炎性细胞因子白细胞介素-1 β（IL-1）的表达，导致涉及蛋白酶Adam 17的诱导和表皮调节蛋白的脱落的级联事件，然后表皮调节蛋白作用于巨噬细胞以诱导肿瘤相关的巨噬细胞表型。 提出了以下具体目标：1）确定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型下游靶点。 2)使用体外和体内模型评价乳腺上皮细胞衍生的Ereg调节巨噬细胞活性的能力。 3)确定ErbB 4/Stat 5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，它们将进一步定义肿瘤形成早期阶段的巨噬细胞功能，从而鉴定出可用于早期乳腺肿瘤诊断和治疗的新型标志物。 从长远来看，乳腺癌高危患者可能会受益于特定的抗炎治疗，可用于抑制肿瘤的形成和进展。 公共卫生相关性：拟议的研究重点是了解炎症的作用，特别强调巨噬细胞在促进乳腺癌发生中的作用。 这项研究与人类健康有关，因为了解人类乳腺癌的启动和促进机制将最终导致为高风险和早期乳腺癌患者开发新的治疗策略。

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. PUBLIC HEALTH RELEVANCE: The proposed studies focus on understanding the role of inflammation, with a specific emphasis on macrophages, in promoting breast cancer initiation. This research is relevant to human health because understanding the mechanisms underlying the initiation and promotion of human breast cancer will ultimately lead to the development of novel therapeutic strategies for high risk and early-stage breast cancer patients.