Immune diagnostics and vaccine targets: breast cancer antigens from mice to women

描述（由申请人提供）：其肿瘤模型人类乳腺癌的转基因小鼠已被证明与人类疾病具有许多分子相似性，并且免疫完整。与患有乳腺癌的人类相似，小鼠也会产生针对癌症相关蛋白的低水平免疫反应。肿瘤特异性免疫的检测将允许开发能够识别与癌症“暴露”相关的标记物的测定方法，从而作为潜在的诊断生物标记物。此外，在恶性转化早期成为免疫原性的蛋白质可能是开发癌症预防疫苗的理想候选者。本申请中描述的初步研究已经证明，转基因小鼠将产生的肿瘤特异性免疫，在很大程度上反映了人类乳腺癌患者的免疫原库，因此，乳腺癌转基因小鼠模型为发现和测试癌症诊断和预防性疫苗的潜在免疫靶点提供了一种工具。我们将集中精力研究两种乳腺癌转基因模型；TgMMTV-neu和TgC3(I)-Tag小鼠。tgmmtv - new动物显示了一种典型的人类腔内乳腺癌的分子表型，占所有人类乳腺癌的近2/3。因此，在这种动物身上发现的标记物对乳腺癌的诊断和治疗具有广泛的适用性。TgC3(I)-Tag小鼠与基底细胞表型具有分子相似性。这些动物加在一起可能代表了大多数人类乳腺癌。此应用程序的目的是：(1)在发生乳腺癌的转基因小鼠中鉴定与癌症起始相关的免疫原性蛋白，可能作为人类乳腺癌的候选诊断靶点和疫苗靶点；(2)确定转基因小鼠中与癌症起始相关的免疫原性蛋白是否在乳腺癌患者中引起类似的抗体免疫，并可用于区分该疾病患者和对照组；(3)确定由转基因小鼠体内致癌相关免疫原性蛋白组成的疫苗能否安全预防乳腺癌的发展，能否鉴定出适合于人类预防性乳腺癌疫苗的抗原表位。在小鼠和人类乳腺癌中表达的蛋白质可以激活免疫反应，并且在分子上是相似的。我们计划在小鼠中鉴定免疫刺激乳腺癌蛋白，并确定它们是否可以预防疾病或抑制肿瘤生长。然后，我们将看到它们的人类同源物是否能激活免疫反应，并有可能用作人类乳腺癌的生物标志物。

DESCRIPTION (provided by applicant): Transgenic mice whose tumors model human breast cancer have been shown to have many molecular similarities to human disease and are immunologically intact. Similar to humans with breast cancer, mice develop low level immune responses directed against cancer associated proteins. Detection of tumor specific immunity will allow the development of assays that may be able to identify markers associated with cancer "exposure", thus, serve as potential diagnostic biomarkers. Furthermore, proteins that become immunogenic early in the malignant transformation may be ideal candidates for the development of vaccines for cancer prevention. Preliminary studies, described in this application, have demonstrated the tumor specific immunity that will arise in transgenic mice significantly mirrors the immunogenic repertoire of human patients with breast cancer and, as such, transgenic mouse models of breast cancer provide an instrument of both discovery and testing of potential immunologic targets for cancer diagnosis and preventative vaccines. We will focus our efforts on two transgenic models of breast cancer; the TgMMTV-neu and TgC3(I)-Tag mouse. The TgMMTV-neu animal demonstrates a molecular phenotype that is typical of human luminal breast cancer which accounts for nearly 2/3 of all human breast cancers. Thus, markers discovered in this animal would have broad applicability to breast cancer diagnosis and treatment. The TgC3(I)-Tag mouse has molecular similarity to a basal cell phenotype. Together these animals could potentially represent the majority of all human breast cancers. The aims of this application are to: (1) identify immunogenic proteins associated with cancer initiation in transgenic mice developing breast cancer that may serve as candidate diagnostic and vaccine targets for human breast cancer, (2) determine whether immunogenic proteins associated with cancer initiation in transgenic mice elicit similar antibody immunity in breast cancer patients and can be used to discriminate patients with the disease from controls, and (3) determine whether a vaccine composed of immunogenic proteins associated with cancer initiation in transgenic mice can safely prevent the development of breast cancer and whether antigenic epitopes suitable for a human preventative breast cancer vaccine can be identified. Proteins expressed on mouse and human breast cancers can activate immune responses, and are molecularly similar. We plan to identify immune stimulatory breast cancer proteins in mice, and determine whether they can prevent disease or inhibit tumor growth. Then, we will see whether their human homologs can activate immune responses and potentially be used as biomarkers of breast cancer in humans.