MALIGNANCY ANTIGENS IN BREAST CANCER

这个项目的长期目标是了解免疫机制。 控制乳腺癌侵袭性(恶性)的药物。其中一个 由恶变引发的最早变化是戏剧性的 细胞表面突起、内陷和脱落膜的形成 表达活性细胞外基质降解的小泡，血浆 膜相关蛋白水解酶，包括胶原酶。初步数据 这表明，在已建立的具有不同侵袭力的细胞系中， 这些膜蛋白在分化的细胞中下调，上调- 在良性激素依赖型乳腺癌中受到调节，并且过度- 在侵袭性激素非依赖性乳腺细胞表面的表达 癌症。关于这些新发现的分子的基本信息不是 可用。这项应用的目的将集中在分子上 乳腺癌膜蛋白的鉴定。四个具体目标 主要有：(1)膜蛋白水解酶的分子鉴定 包括它们的多肽和基因的特性，(2)到 确定膜蛋白水解酶在相互作用中的作用 胶原酶在局部基底膜降解中的作用 实验动物或乳腺癌患者，以及(3)评估 通过(A)检测作为相关乳腺癌抗原的膜蛋白 实验动物或乳腺癌中可能的免疫反应 患者包括T淋巴细胞的激活，以及(B)其基因的测定 在体内外恶性转化过程中的表达 乳腺癌的模型。这些目标检验了恶性的假设 乳腺细胞的转化导致膜的特异性表达 细胞表面的蛋白水解酶，可能调节细胞的入侵 上皮细胞穿过其底层的基底膜和基质 也导致了基质-上皮相互作用的重要变化 就像免疫反应一样。这项研究的结果可以导致 制定有效的免疫预防策略 或乳腺癌的治疗。

The long term goal of this project is to understand the immune mechanisms that control breast cancer invasiveness (malignancy). One of the earliest changes triggered by malignant transformation is the dramatic formation of cell surface protrusions, invadopodia, and shed membrane vesicles that express active extracellular matrix-degrading, plasma membrane-associated proteases including collagenases. Preliminary data indicate that, in established cell lines with differential invasiveness, these membrane proteases are down-regulated in differentiated cells, up- regulated in benign hormone-dependent breast carcinoma, and over- expressed on the cell surface of invasive hormone-independent breast carcinoma. Basic information on these newly discovered molecules is not available. The aims of this application will focus on the molecular identification of breast cancer membrane proteases. Four specific aims are: (1) to perform the molecular identification of membrane proteases including characterization of their polypeptides and genes, (2) to determine the functional role of membrane proteases in interacting with collagenases during localized basement membrane degradation and in experimental animals or breast cancer patients, and (3) to evaluate membrane proteases as relevant breast cancer antigens by (a) examining possible immune responses in experimental animals or breast cancer patients including T lymphocyte activation, and (b) determining its gene expression during malignant transformation in the in vitro and in vivo models of breast cancers. These aims test the hypothesis that malignant transformation of breast cells leads to specific expression of membrane proteases on the cell surface, that may regulate the invasion of epithelial cells through their underlying basement membrane and stroma leading to important changes in stromal-epithelial interactions as well as in immune responses. The results of this study can lead to the development of effective strategies for immunologically-based prevention or treatment of breast cancer.