ephrin-A1 in lipogenesis and breast cancer metastatic progression

描述(申请人提供)：乳腺癌是西方女性最常见的恶性肿瘤。虽然辅助性和分子靶向治疗显著提高了患者的存活率，但乳腺癌转移仍然是无法治愈的，是女性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发现，EphA2受体酪氨酸激酶是一个有希望的靶点。我们和其他人发现，EphA2在大约60%的人类乳腺癌标本中过表达，包括耐药的HER2阳性肿瘤和三阴性/基底细胞样乳腺癌，这与较低的生存率相关。切除小鼠的EphA2抑制了HER依赖的MMTV-Neu乳腺肿瘤模型的转移进展。相反，EphA2的原型配体EphA1在淋巴转移患者中经常丢失表达，高水平的Ephin-A1与转移性疾病患者更好的生存相关，这表明配体依赖的信号抑制了EphA2依赖的肿瘤进展和转移扩散。因此，我们假设EPhin-A1作为一个分子开关，从而使EphA2的功能从抑制肿瘤转变为促进肿瘤。我们准备在我们新生成的ephin-A1-空小鼠模型中测试这个模型。在这项提案中，我们将测试ePhin-A1配体在小鼠乳腺癌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ePhin-A1作为预测人类乳腺癌转移相对风险的新的预后标志物。我们还将使用遗传学方法和选择性的EphA2激酶抑制剂(AIM 1)来确定EphA2是否是由于EPhin-A1缺失而导致的肿瘤进展和转移所必需的。作为研究ePhin-A1抑制乳腺癌进展的机制的第一步，我们发现在ePhin-A1-Null/MMTV-Neu肿瘤中，脂肪酸合成酶(FASN)的表达和脂质含量增加，以及谷氨酰胺分解增加。由于脂质和谷氨酰胺代谢在乳腺癌的发病机制中起作用，我们将确定通过EPhin/Eph信号对脂肪生成和谷氨酰胺分解的分子调控是否有助于体内的生长和转移(目标2)。该项目的成功不仅将阐明控制EphA2 RTK促进肿瘤和抑制肿瘤之间切换的分子机制，而且还将验证新型EphA2靶向选择性激酶抑制剂用于治疗目前治疗方案无效的乳腺癌亚型，如三阴性/基底样样乳腺癌 或对抗HER2药物产生抗药性的HER2阳性癌症。此外，这项建议还解决了NCI在癌症生物学中强调的几个领域，包括“癌基因成瘾”和“肿瘤新陈代谢/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".