ephrin-A1 in lipogenesis and breast cancer metastatic progression

描述（由申请人提供）：乳腺癌是西方妇女中最常见的恶性肿瘤。虽然辅助和分子靶向治疗显着提高患者的生存率，乳腺癌转移仍然是不可治愈的，是妇女发病率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确定EphA 2受体酪氨酸激酶为有希望的靶点。我们和其他人发现EphA 2在约60%的人类乳腺癌标本中过表达，包括耐药HER 2阳性肿瘤和三阴性/基底样乳腺癌，与生存率低相关。小鼠中EphA 2的消融抑制了HER依赖性MMTV-Neu乳腺肿瘤模型中的转移进展。相比之下，ephrin-A1（EphA 2的原型配体）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存活相关，这表明配体依赖性信号传导抑制EphA 2依赖性肿瘤进展和转移扩散。因此，我们假设肝配蛋白-A1作为一个分子开关，使肝配蛋白的损失EphA 2的功能从肿瘤抑制转化为肿瘤促进。我们准备在我们新生成的ephrin-A1-null小鼠模型中测试该模型。在这项提案中，我们将测试ephrin-A1配体在小鼠乳腺肿瘤生长和转移中的抑制作用及其作为转移性乳腺癌生物标志物的价值，最终目标是开发ephrin-A1作为预测人类乳腺癌转移相对风险的新预后标志物。我们还将使用遗传方法和选择性EphA 2激酶抑制剂来确定EphA 2是否是肝配蛋白-A1缺失诱导的肿瘤进展和转移所必需的（Aim 1）。作为研究ephrin-A1抑制乳腺癌进展的机制的第一步，我们发现了脂肪酸合成酶（Festival）表达和脂质含量的升高，以及ephrin-A1-null/MMTV-Neu肿瘤中的精氨酸分解增加。由于脂质和谷氨酰胺代谢有助于乳腺癌的发病机制，我们将确定通过肝配蛋白/Eph信号传导对脂肪生成和谷氨酰胺分解的分子调控是否有助于体内生长和转移（目的2）。该项目的成功不仅将阐明通过EphA 2 RTK控制肿瘤促进与肿瘤抑制之间转换的分子机制，而且还将验证新型EphA 2靶向选择性激酶抑制剂用于治疗目前治疗难治的乳腺癌亚型，例如三阴性/基底样乳腺癌 或对抗HER 2剂产生耐药性的HER 2阳性癌症。此外，该提案还涉及NCI在癌症生物学中的“挑衅性问题”中强调的几个领域，包括“致癌基因成瘾”和“肿瘤代谢/肥胖对癌症的影响”。

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".