Fatty Acid Synthase /Molecular Target /Breast Cancer The

脂肪酸合酶/分子靶标/乳腺癌

• 批准号: 6964059
• 负责人: RUTH LUPU
• 金额: $ 41.67万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-16 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6964059
• 关键词: antineoplastics; athymic mouse; breast neoplasms; cancer prevention; cell growth regulation; cell line; chemoprevention; clinical research; drug resistance; enzyme activity; fatty acid synthase; female; gene expression; human genetic material tag; human tissue; lipid biosynthesis; mammary epithelium; molecular oncology; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplastic process; neoplastic transformation; oncogenes; preneoplastic state; protein structure function; serology /serodiagnosis

DESCRIPTION (provided by applicant): There are two sources of fatty acids for animals, exogenous (dietary) fatty acids and de novo endogenous biosynthesis, of which the latter is regulated by Fatty Acid Synthase (FAS). The high level of fat in the Western diet has been implicated in the development of many human malignancies, including breast cancer. Indeed, dietary fatty acids have emerged as an intense focus of research and controversy in breast cancer etiology, prevention and/or therapy. Human breast cancer cell lines and breast tumors exhibit overexpression and hyperactivity of FAS, with FAS-overexpressing breast cancer tumors demonstrating shortened disease-free intervals or overall survivals. Moreover, FAS overexpression can also be identified in intraductal and lobular in situ breast carcinoma, pre-neoplastic lesions associated with increased risk for the development of infiltrating breast cancer, while elevated serum FAS levels have been identified in breast cancer patients with different clinical stages compared with healthy subjects. Interestingly, the relative absence of endogenous fatty acid biosynthesis in normal tissues has led to the notion that FAS blockade should provide a highly selective basis for anticancer therapy. These data, altogether, reveal that FAS-dependent de novo fatty biogenesis, an anabolic energy-storage pathway largely considered of minor importance in humans, may ultimately be used for diagnosis, prognosis, early intervention, and treatment of breast carcinomas. As a part of our efforts to assess the role of FAS signaling on the survival and proliferation of human breast cancer cells, we have identified a novel bi-directional molecular link between breast cancer-associated FAS and Her-2/neu oncogene. A positive correlation was found between high levels of FAS expression and the amplification and/or overexpression of Her-2/neu oncogene. Pharmacological inhibition of FAS by the natural mycotoxin cerulenin, or a related synthetic compound, C75 or a statin Orlistat, negatively regulated Her-2/neu-encoded p185Her-2/neu oncoprotein and its associated tyrosine-kinase activity. When FAS gene expression was silenced by RNA interference (RNAi) a dramatic decrease of p185Her-2/neu expression occurred in the Her-2/neu-overexpressing cells, whereas there was no effect in cells expressing physiological levels of Her-2/neu. Remarkably, pharmacological and RNAi mediated downregulation of Her-2/neu and, concomitantly, caused a prominent up-regulation of PEA3, a transcriptional represser of Her-2/neu. Furthermore, a simultaneous targeting of FAS and Her-2/neu signaling by chemical FAS inhibitors and the humanized monoclonal antibody directed against p185Her-2/neu trastuzumab (Herceptin(tm)), resulted in a synergistic growth inhibitory effect towards Her-2/neu overexpressing cells. These findings support the hypothesis that breast cancer-associated FAS, rather than simply the epigenetic consequence of aberrant activation of up-stream transduction pathways (e.g. PI-3K/AKT, Ras/Raf/MEK/ERK) plays an active role in breast cancer evolution by regulating oncogenic proteins closely related to malignant transformation. Indeed, our pioneer observations demonstrating the ability of FAS-driven signaling to regulate the expression and/or activity of Her-2/neu (erbB-2) oncogene strongly suggest that FAS may actively participate in the triggering, maintenance and/or enhancement of the breast cancer malignant phenotype. Therefore our aims are: 1) To characterize the molecular mechanism determining the early up-regulation of FAS in breast cancer and to evaluate the oncogenic potential of FAS-catalyzed endogenous lipogenesis in normal breast epithelial cell models. We will determine how FAS contributes to the pre-neoplastic transformation of noncommittal breast epithelial cells (normal cells) and whether FAS overexpression sets off malignant transformation. 2) To evaluate the therapeutic relevance of targeting FAS in Her-2/neu-overexpressing breast cancer in vitro and in vivo on the basis of the novel bidirectional molecular link between FAS and the Her-2/neu that we recently demonstrated. 3) We will characterize the molecular mechanisms underlying the bi-directional molecular cross-talk between FAS and Her-2/neu. In addition, we will assess whether FAS blockade represents a novel sensitizing strategy to reverse trastuzumab (Herceptin(tm)) resistance in Her-2/neu-overexpressing breast carcinomas. 4) To evaluate whether inhibition of FAS activity modulates breast cancer cell sensitivity to chemotherapy-induced cell damage and to evaluate whether silencing FAS expression modulates breast cancer cell sensitivity to chemotherapy-induced cell damage. 5) To determine the molecular relevance and clinical impact of FAS expression in breast cancer progression, and to evaluate the value and clinical contribution to the treatment decision provided by the assessment of circulating serum levels of FAS. Our study speculates that constitutive up-regulation of FAS in breast cancer disease represents an early metabolic response for survival to the hypoxic and acidic microenvironment of pre-malignant breast cancer phases. This epigenetic up-regulation of FAS in early stages of breast cancer may result, in turn, in a metabolic strategy of selection to maintain high proliferation rates of surviving cells. The characterization of FAS as a novel metabolic oncogene will allow an invaluable adjunct to gene expression profiling or proteomics in the characterization of biologically aggressive subsets of breast carcinomas. Moreover, the predictive potential of measurement FAS expression will help in the selection of better responders to cytotoxic drugs, and Her-2/neu-targeted therapies. Considering that drug resistance hampers successful breast cancer treatment, and its prevention or reversal is still awaiting new sensitizing strategies or pharmaceuticals, our study will open a new molecular avenue based on the specific targeting of FAS-dependent neoplastic lipogenesis, a valuable specific molecular target that is minimally activated in normal tissues.

描述（申请人提供）：动物的脂肪酸有两种来源，外源（膳食）脂肪酸和从头内源生物合成，其中后者受脂肪酸合酶（FAS）调节。西方饮食中的高脂肪含量与许多人类恶性肿瘤的发生有关，包括乳腺癌。事实上，膳食脂肪酸已成为乳腺癌病因学、预防和/或治疗领域研究和争议的焦点。人类乳腺癌细胞系和乳腺肿瘤表现出 FAS 的过度表达和过度活跃，其中 FAS 过度表达的乳腺癌肿瘤表现出无病间隔或总生存期缩短。此外，FAS过表达也存在于导管内和小叶原位乳腺癌中，这些癌前病变与浸润性乳腺癌发展风险增加相关，而不同临床分期的乳腺癌患者血清FAS水平升高。与健康受试者。有趣的是，正常组织中相对缺乏内源性脂肪酸生物合成，因此人们认为 FAS 阻断应该为抗癌治疗提供高度选择性的基础。这些数据总的来说表明，FAS 依赖性从头脂肪生物合成（一种合成代谢能量储存途径，在很大程度上被认为对人类不太重要）可能最终用于乳腺癌的诊断、预后、早期干预和治疗。作为评估 FAS 信号传导对人类乳腺癌细胞存活和增殖作用的努力的一部分，我们发现了乳腺癌相关 FAS 和 Her-2/neu 癌基因之间的一种新型双向分子联系。发现高水平的 FAS 表达与 Her-2/neu 癌基因的扩增和/或过度表达之间呈正相关。天然霉菌毒素浅蓝菌素或相关合成化合物 C75 或他汀类奥利司他对 FAS 的药理学抑制作用，负向调节 Her-2/neu 编码的 p185Her-2/neu 癌蛋白及其相关的酪氨酸激酶活性。当 FAS 基因表达被 RNA 干扰 (RNAi) 沉默时，Her-2/neu 过表达细胞中 p185Her-2/neu 表达急剧下降，而表达生理水平 Her-2/neu 的细胞则没有影响。 。值得注意的是，药理学和 RNAi 介导 Her-2/neu 的下调，同时引起 PEA3（Her-2/neu 的转录抑制因子）的显着上调。此外，化学 FAS 抑制剂和针对 p185Her-2/neu 曲妥珠单抗（Herceptin(tm)）的人源化单克隆抗体同时靶向 FAS 和 Her-2/neu 信号传导，导致对 Her-2/ neu 过表达细胞。这些发现支持这样的假设：与乳腺癌相关的 FAS，而不仅仅是上游转导途径（例如 PI-3K/AKT、Ras/Raf/MEK/ERK）异常激活的表观遗传结果，在乳腺癌中发挥着积极作用。通过调节与恶性转化密切相关的致癌蛋白来进化。事实上，我们的先驱观察表明 FAS 驱动的信号传导能够调节 Her-2/neu (erbB-2) 癌基因的表达和/或活性，强烈表明 FAS 可能积极参与触发、维持和/或增强乳腺癌的恶性表型。因此，我们的目标是：1）表征乳腺癌中FAS早期上调的分子机制，并评估正常乳腺上皮细胞模型中FAS催化的内源性脂肪生成的致癌潜力。我们将确定 FAS 如何促进非定型乳腺上皮细胞（正常细胞）的肿瘤前转化，以及 FAS 过度表达是否会引发恶性转化。 2) 基于我们最近证明的 FAS 和 Her-2/neu 之间的新型双向分子联系，在体外和体内评估靶向 FAS 在 Her-2/neu 过表达乳腺癌中的治疗相关性。 3) 我们将描述 FAS 和 Her-2/neu 之间双向分子串扰的分子机制。此外，我们将评估 FAS 阻断是否代表一种新的敏化策略，可逆转 Her-2/neu 过表达乳腺癌中的曲妥珠单抗（赫赛汀 (tm)）耐药性。 4)评估FAS活性的抑制是否调节乳腺癌细胞对化疗引起的细胞损伤的敏感性，并评估沉默FAS表达是否调节乳腺癌细胞对化疗引起的细胞损伤的敏感性。 5) 确定FAS表达在乳腺癌进展中的分子相关性和临床影响，并评估评估FAS循环血清水平所提供的治疗决策的价值和临床贡献。我们的研究推测，乳腺癌疾病中 FAS 的组成性上调代表了乳腺癌恶变前阶段对缺氧和酸性微环境生存的早期代谢反应。乳腺癌早期阶段 FAS 的这种表观遗传上调可能会导致代谢选择策略，以维持存活细胞的高增殖率。 FAS 作为一种新型代谢癌基因的表征将成为基因表达谱或蛋白质组学的宝贵辅助手段，用于表征乳腺癌的生物侵袭性子集。此外，测量 FAS 表达的预测潜力将有助于选择对细胞毒性药物和 Her-2/neu 靶向治疗有更好反应的患者。考虑到耐药性阻碍了乳腺癌的成功治疗，其预防或逆转仍需新的敏化策略或药物，我们的研究将基于FAS依赖性肿瘤性脂肪生成的特异性靶向开辟一条新的分子途径，FAS依赖性肿瘤性脂肪生成是一个有价值的特定分子靶点在正常组织中被最低程度地激活。