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

描述（由申请人提供）：转基因小鼠的肿瘤模型人乳腺癌已被证明具有许多分子相似性，人类疾病和免疫完整。与患有乳腺癌的人类相似，小鼠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”相关的标志物的测定方法，从而作为潜在的诊断生物标志物。此外，在恶性转化早期变得具有免疫原性的蛋白质可能是用于开发癌症预防疫苗的理想候选物。在本申请中描述的初步研究已经证明，将在转基因小鼠中产生的肿瘤特异性免疫力显著反映了患有乳腺癌的人类患者的免疫原性库，并且因此，乳腺癌的转基因小鼠模型提供了发现和测试用于癌症诊断和预防性疫苗的潜在免疫学靶标的工具。我们将集中精力研究两种乳腺癌转基因模型：TgMMTV-neu和TgC 3（I）-Tag小鼠。TgMMTV-neu动物表现出一种典型的人管腔型乳腺癌的分子表型，占所有人乳腺癌的近2/3。因此，在这种动物中发现的标记物将对乳腺癌的诊断和治疗具有广泛的适用性。TgC 3（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所有人类乳腺癌的大多数。本申请的目的是：（1）鉴定与发生乳腺癌的转基因小鼠中的癌症起始相关的免疫原性蛋白质，其可用作人乳腺癌的候选诊断和疫苗靶标，（2）确定与转基因小鼠中的癌症起始相关的免疫原性蛋白质是否在乳腺癌患者中引发类似的抗体免疫，并可用于区分患有该疾病的患者与对照，和（3）确定由与转基因小鼠中癌症起始相关的免疫原性蛋白质组成的疫苗是否可以安全地预防乳腺癌的发展，以及是否可以鉴定适合于人预防性乳腺癌疫苗的抗原表位。在小鼠和人类乳腺癌上表达的蛋白质可以激活免疫反应，并且在分子上相似。我们计划在小鼠中鉴定免疫刺激性乳腺癌蛋白，并确定它们是否可以预防疾病或抑制肿瘤生长。然后，我们将观察它们的人类同源物是否可以激活免疫反应，并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.