ephrin-A1 in lipogenesis and breast cancer metastatic progression

ephrin-A1 在脂肪生成和乳腺癌转移进展中的作用

基本信息

批准号：
9935241
负责人：
DANA M BRANTLEY-SIEDERS
金额：
$ 4.69万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-14 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9935241
关键词：
Ablation Address Adjuvant Adjuvant Therapy Affect Animals Area Binding Biological Markers Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Breast cancer metastasis Cancer Biology Cause of Death Cell Proliferation Cell surface Cells Cessation of life Collaborations Disease Drug resistance ERBB2 gene Enzymes Eph Family Receptors EphA2 Receptor Ephrin-A1 Ephrins Epithelial Excision Fatty-acid synthase Glutamine Goals Growth Human Hyperplasia Investigation Knockout Mice Lesion Ligands Link Lipids Malignant Neoplasms Mammary Neoplasms Mammary gland Mass Spectrum Analysis Mediating Metabolism Metastatic Neoplasm to Lymph Nodes Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Molecular Morbidity - disease rate Mouse Mammary Tumor Virus Mus Neoplasm Metastasis Obesity Oncologist Pathogenesis Patients Pharmaceutical Chemistry Pharmacology Phenotype Population Positive Lymph Node Primary Neoplasm Prognostic Marker Receptor Signaling Refractory Regulation Relative Risks Resistance development Role Series Signal Pathway Signal Transduction Specimen Testing Therapeutic Therapeutic Agents Translating Tumor Promotion Tumor Suppression Universities Woman Work breast cancer progression cancer cell cancer subtypes cancer therapy cooking effective therapy experimental study genetic approach genome-wide analysis high risk improved in vivo individual patient individualized medicine inhibitor/antagonist innovation insight kinase inhibitor knock-down lipid biosynthesis loss of function malignant breast neoplasm mammary gland development mass flux molecular targeted therapies mouse model multidisciplinary neoplastic neoplastic cell new therapeutic target novel oncogene addiction overexpression predictive marker public health relevance side effect success treatment strategy tumor tumor growth tumor metabolism tumor progression

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is the most common malignancy among western women. Although adjuvant and molecularly targeted therapies significantly improve patient survival, breast cancer metastasis remains incurable and is the main cause of morbidity and cancer death in women. Recent genome-wide analysis of human breast cancer identified EphA2 receptor tyrosine kinase as a promising target. We and others found that EphA2 is overexpressed in ~60% of human breast cancer specimens, including drug-resistant HER2 positive tumors and triple-negative/basal-like breast cancer, correlating with poor survival. Ablation of EphA2 in mice inhibited metastatic progression in the HER-dependent MMTV-Neu mammary tumor model. In contrast, expression of ephrin-A1, the prototypic ligand for EphA2, is frequently lost in lymph node metastasis patients and high levels of ephrin-A1 correlates with better survival in patients with metastatic disease, suggesting that ligand-dependent signaling inhibits EphA2-dependent tumor progression and metastatic spread. Therefore, we hypothesize that ephrin-A1 acts as a molecular switch, such that loss of ephrin converts EphA2 functions from tumor suppression to tumor promotion. We are poised to test this model in our newly generated ephrin-A1-null mouse model. In this proposal, we will test the inhibitory role of ephrin-A1 ligand in mammary tumor growth and metastasis in mice and its value as a biomarker for metastatic breast cancer, with the ultimate goal of developing ephrin-A1 as a new prognostic marker for predicting the relative risk of human breast cancer metastasis. We will also determine if EphA2 is required for tumor progression and metastasis induced by loss of ephrin-A1, using both a genetic approach and a selective EphA2 kinase inhibitor (Aim 1). As a first step in investigating the mechanism through which ephrin-A1 inhibits breast cancer progression, we discovered elevated fatty acid synthase (FASN) expression and lipid content, as well as increased glutaminolysis in ephrin-A1-null/MMTV-Neu tumors. Since lipid and glutamine metabolism contributes to breast cancer pathogenesis, we will determine if molecular regulation of lipogenesis and glutaminolysis by ephrin/Eph signaling contributes to growth and metastasis in vivo (Aim 2). Success of this project will not only elucidate the molecular mechanisms that control the switch between tumor promotion versus tumor suppression by EphA2 RTK, but also validate novel EphA2-targeting selective kinase inhibitors for treatment of breast cancer subtypes that are refractory to current therapies, such as triple-negative/basal-like breast cancer or HER2 positive cancers that developed resistance to anti-HER2 agents. In addition, this proposal addresses several areas emphasized in the NCI's "provocative questions" in cancer biology, including "oncogene addiction" and "tumor metabolism/obesity's influences on cancer".

描述（由申请人提供）：乳腺癌是西方女性中最常见的恶性肿瘤。尽管辅助和分子靶向治疗显着提高了患者的生存率，但乳腺癌转移仍然无法治愈，并且是女性发病和癌症死亡的主要原因。最近对人类乳腺癌的全基因组分析发现 EphA2 受体酪氨酸激酶是一个有前途的靶点。我们和其他人发现 EphA2 在约 60% 的人类乳腺癌样本中过度表达，包括耐药 HER2 阳性肿瘤和三阴性/基底样乳腺癌，与较差的生存率相关。消除小鼠中的 EphA2 可抑制 HER 依赖性 MMTV-Neu 乳腺肿瘤模型的转移进展。相比之下，EphA2 的原型配体 ephrin-A1 的表达在淋巴结转移患者中经常丢失，并且高水平的 ephrin-A1 与转移性疾病患者的更好生存相关，这表明配体依赖性信号传导抑制 EphA2 依赖性肿瘤进展和转移扩散。因此，我们假设ephrin-A1充当分子开关，使得ephrin的缺失将EphA2的功能从肿瘤抑制转变为肿瘤促进。我们准备在新生成的 ephrin-A1-null 小鼠模型中测试该模型。在本提案中，我们将测试ephrin-A1配体对小鼠乳腺肿瘤生长和转移的抑制作用及其作为转移性乳腺癌生物标志物的价值，最终目标是将ephrin-A1开发为预测新的预后标志物人类乳腺癌转移的相对风险。我们还将使用遗传方法和选择性 EphA2 激酶抑制剂来确定 EphA2 是否是肝配蛋白-A1 缺失引起的肿瘤进展和转移所必需的（目标 1）。作为研究 ephrin-A1 抑制乳腺癌进展机制的第一步，我们发现 ephrin-A1-null/MMTV-Neu 肿瘤中脂肪酸合酶 (FASN) 表达和脂质含量升高，以及谷氨酰胺分解增加。由于脂质和谷氨酰胺代谢有助于乳腺癌发病机制，因此我们将确定肝配蛋白/Eph 信号传导对脂肪生成和谷氨酰胺分解的分子调节是否有助于体内生长和转移（目标 2）。该项目的成功不仅将阐明控制 EphA2 RTK 促进肿瘤与抑制肿瘤之间转换的分子机制，还将验证新型 EphA2 靶向选择性激酶抑制剂用于治疗现有疗法难以治愈的乳腺癌亚型，例如三阴性/基底样乳腺癌或对抗 HER2 药物产生耐药性的 HER2 阳性癌症。此外，该提案还涉及 NCI 在癌症生物学“挑衅性问题”中强调的几个领域，包括“癌基因成瘾”和“肿瘤代谢/肥胖对癌症的影响”。