Progression of DCIS to Invasive Breast Cancer through CCR2 Chemokine Signaling

摘要 在美国，每年约有50，000例导管原位癌（DCIS）被诊断出来，使DCIS成为全球最严重的乳腺癌。 最常见的类型的非侵入性乳腺癌诊断的妇女。高达20%的患者会经历 疾病复发伴有浸润性导管癌（IDC）。当前细胞和组织病理学 这些方法不能准确预测疾病进展，导致患者治疗不足或过度， 治疗DCIS我们的长期目标是确定导致IDC的关键因素， 一种基于分子的方法来预测IDC的风险，以及一种更适合治疗DCIS的方法。的 趋化因子受体CCR 2是G蛋白偶联受体，其通常在巨噬细胞上表达， 在炎症和癌症进展过程中调节对CCL 2的趋化性。使用乳房 为了在动物中模拟DCIS形成，我们挑战了当前的范式 通过证明CCL 2/CCR 2信号传导至乳腺癌细胞促进DCIS， 发展到IDC。该R 01更新项目描述了代谢和c-MET在CCL 2/CCR 2中的作用 介导的DCIS进展，并可能识别DCIS进展的更好预测标志物， 减少患者过度治疗，并为开发CCR 2作为治疗靶点提供依据， 减少治疗不足。代谢重编程是癌症的一个重要标志，但人们对此知之甚少 早期乳腺癌初步研究表明，CCL 2/CCR 2增强DCIS进展是一个重要的机制。 与糖酵解和谷氨酰胺代谢增加有关，这有助于脂肪酸合成。CCL2 介导的乳腺癌侵袭和代谢可能依赖于CCR 2和c- 乳腺癌细胞中的MET受体酪氨酸激酶。我们假设，CCL 2/CCR 2趋化因子信号转导在 乳腺癌细胞通过c-MET依赖性机制增强葡萄糖和谷氨酰胺代谢， 促进DCIS进展。目的1.确定CCL 2、CCR 2、c-MET与代谢酶的相关性 使用患者样本和磁共振检测DCIS向浸润性癌进展的表达 在携带DCIS的动物中的成像/光谱方法。目的2是确定的功能贡献 c-MET通过调节c-MET/CCL 2/CCR 2介导的乳腺癌生长、存活、侵袭和代谢， MET在体外乳腺癌细胞和MIND模型中的作用。CCR 2/c-MET/SRC相互作用的机制 将通过分子和生物化学方法检查乳腺癌细胞系。目标3：确定 CCL 2/CCR 2介导的代谢变化促进的生物化学和分子机制 糖酵解、谷氨酰胺和脂肪酸合成对乳腺癌生长、存活和侵袭的调节作用 在生物化学和细胞培养测定中，乳腺癌细胞中的信号通路。蛋白质降解途径， 潜在地调节乳腺癌细胞中的HKII、GLS 1和FGFR 1表达将通过以下方式进行检查： 生物化学方法。

ABSTRACT About 50,000 cases of ductal carcinoma in situ (DCIS) are diagnosed in the US every year, making DCIS the most common type of non-invasive breast cancer diagnosed in women. Up to 20% of all patients will experience disease recurrence accompanied by invasive ductal carcinoma (IDC). Current cyto- and histopathological approaches do not accurately predict disease progression, resulting in patients being under-treated or over- treated for DCIS. Our long-term goals are to identify key factors that lead to IDC that will enable the development of a molecular based approach to predict the risk of IDC, and a more tailored approach to treat DCIS. The chemokine receptor CCR2 is a G Protein Coupled Receptor, which is normally expressed on macrophages and regulates chemotaxis in response to CCL2 during inflammation and cancer progression. Using a mammary intraductal injection model (MIND) to mimic DCIS formation in animals, we have challenged current paradigms on CCL2/CCR2 signaling, by demonstrating that CCL2/CCR2 signaling to breast cancer cells promotes DCIS progression to IDC. This R01 renewal project characterizes the role of metabolism and c-MET in CCL2/CCR2 mediated DCIS progression, and may identify better predictive markers for DCIS progression, with implications on reducing patient over-treatment, and provide justification for developing CCR2 as a therapeutic target to reduce under-treatment. Metabolic reprogramming is an important hallmark of cancer, but is poorly understood in early stage breast cancer. Preliminary studies indicate that CCL2/CCR2 enhancement of DCIS progression is associated with increased glycolysis and glutamine metabolism, which facilitate fatty acid synthesis. CCL2 mediated breast cancer invasiveness and metabolism may be dependent on interactions between CCR2 and c- MET receptor tyrosine kinases in breast cancer cells. We hypothesize that CCL2/CCR2 chemokine signaling in breast cancer cells enhances glucose and glutamine metabolism through c-MET dependent mechanisms to facilitate DCIS progression. Aim 1 is to determine the relevance of CCL2, CCR2, c-MET and metabolic enzyme expression to DCIS progression to invasive carcinoma using patient samples and magnetic resonance imaging/spectroscopy approaches in DCIS bearing animals. Aim 2 is to determine the functional contribution of c-MET to CCL2/CCR2 mediated breast cancer growth, survival, invasion and metabolism through modulating c- MET in breast cancer cells in vitro and in the MIND model. Mechanisms of CCR2/c-MET/SRC interactions in breast cancer cell lines will be examined through molecular and biochemical approaches. Aim 3 is to determine the biochemical and molecular mechanisms through which CCL2/CCR2 mediated metabolic changes promote breast cancer growth, survival and invasion through modulation of glycolytic, glutamine and fatty acid synthesis pathways in breast cancer cells in biochemical and cell culture assays. Protein degradation pathways that potentially regulate HKII, GLS1 and FASN expression in breast cancer cells will be examined through biochemical approaches.