MALIGNANCY ANTIGENS IN BREAST CANCER

该项目的长期目标是了解免疫机制 控制乳腺癌的侵袭性（恶性）。 之一 最早的变化引发的恶性转化是戏剧性的 细胞表面突起、侵入伪足和脱落膜的形成 表达活性细胞外基质降解的囊泡，血浆 膜相关蛋白酶，包括胶原酶。 初步数据 这表明，在具有不同侵袭力的已建立的细胞系中， 这些膜蛋白酶在分化的细胞中下调，上调， 在良性乳腺癌中调节， 表达于侵袭性乳腺癌非依赖性乳腺癌细胞表面 carcinoma.这些新发现的分子的基本信息并不 available. 本申请的目的将集中在分子水平上。 乳腺癌膜蛋白酶的鉴定。四个具体目标 主要有：（1）进行膜蛋白酶的分子鉴定 包括其多肽和基因的表征，（2） 确定膜蛋白酶在相互作用中的功能作用 胶原酶在局部基底膜降解和 实验动物或乳腺癌患者，以及（3）评估 作为相关乳腺癌抗原的膜蛋白酶， 实验动物或乳腺癌中可能的免疫反应 患者包括T淋巴细胞活化，和（B）确定其基因 在体外和体内恶性转化过程中的表达 乳腺癌的模型。 这些目标验证了恶性肿瘤 乳腺细胞的转化导致膜特异性表达 细胞表面的蛋白酶，可以调节入侵 上皮细胞穿过其下面的基底膜和基质 也导致基质-上皮相互作用的重要变化 就像免疫反应一样。 这项研究的结果可能会导致 制定有效的免疫预防战略 或治疗乳腺癌。

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.