ERB-B-2 EXPRESSION AND RESISTANCE TO TNF KILLING

ERB-B-2 表达和对 TNF 杀伤的抵抗力

• 批准号: 2107491
• 负责人: VISHVA M DIXIT
• 金额: $ 18.2万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2107491
• 关键词: athymic mouse; breast neoplasms; clone cells; gene expression; lymphokine activated killer cell; mammary epithelium; membrane proteins; neoplasm /cancer genetics; neoplasm /cancer immunology; oncogenes; protein tyrosine kinase; tumor necrosis factor alpha

Breast cancer is the most frequently diagnosed cancer in women and the second leading cause of their cancer deaths. Most patients succumb to metastatic disease. A critical component of the metastatic cascade is the development of resistance to host defense mechanisms including tumor cell killing by activated macrophages and natural cytotoxic cells. It is now clear that killing by both these immune effector cells involves tumor necrosis factor (TNF). Indeed, resistance to TNF cytotoxicity has been found to correlate with resistance to killing by macrophages and natural killer cells. Amplified expression of the erb-B-2/HER2 oncogene has been recently found to correlate with resistance to the cytotoxic effects of TNF and tumoricidal macrophages. This suggests a mechanism by which a subset of tumor cells might survive elimination by host immune surveillance, thereby allowing their propagation and eventual spread (metastases). The erbB-2 oncogene (also known as HER2) is a membrane tyrosine kinase that plays an important role in carcinogenesis. It is amplified in approximately 30% of primary breast carcinomas where its expression correlates with a poor prognosis. erbB-2 expression also appears to be important in ovarian cancer where its expression correlated with resistance to killing by TNF and lymphokine-activated killer cells. Preliminary studies suggest that A20, a novel zinc finger protein that confers resistance to TNF killing, is induced by erbB-2 amplification and that this is the mechanism responsible for the resistant phenotype. Given this, the Specific Aims of the grant are as follows: 1. To what extent does A20 contribute to TNF-resistance associated with amplification of the HER2/neu/erbF-2 oncogene in breast cancers? 2. Elucidation of the mechanism by which erbB-2 modulates A20 expression. 3. To determine if there is a relationship between A20 expression and TNF-resistance in vitro among human breast cancer cell lines and in vivo biological behavior in athymic mice. 4. To assess A20 expression in normal and malignant human breast tissue specimens and in normal and malignant breast epithelial cells.

乳腺癌是女性最常见的癌症， 癌症死亡的第二大原因。 大多数病人死于 转移性疾病 转移级联的一个关键组成部分是 对包括肿瘤在内的宿主防御机制产生抗性 通过活化的巨噬细胞和天然的细胞毒性细胞杀死细胞。 它 现在清楚的是，这两种免疫效应细胞的杀伤作用涉及 肿瘤坏死因子（TNF）。 事实上，对TNF细胞毒性的抗性 发现与巨噬细胞杀伤抗性相关， 自然杀伤细胞 erb-B-2/HER 2癌基因的扩增表达 最近发现与对细胞毒性药物的抗性有关。 TNF和杀肿瘤巨噬细胞的作用。 这表明了一种机制 通过这种方法，一部分肿瘤细胞可以在宿主免疫清除后存活下来， 监视，从而使其传播和最终蔓延 （转移）。 erbB-2癌基因（也称为HER 2）是一种膜蛋白， 酪氨酸激酶，在癌症发生中起重要作用。 是 在大约30%的原发性乳腺癌中扩增， 表达与不良预后相关。 erbB-2表达也 在卵巢癌中似乎很重要， 对TNF和淋巴因子激活的杀伤细胞的杀伤有抵抗力。 初步研究表明，A20是一种新的锌指蛋白， 赋予对TNF杀伤的抗性，由erbB-2扩增诱导， 这是导致耐药表型的机制。 有鉴于此，赠款的具体目标如下：1。 什么 A20在多大程度上有助于与 乳腺癌中HER 2/neu/erbF-2癌基因的扩增？ 2. 阐明erbB-2调节A20表达的机制。 3. 为了确定A20表达与 人乳腺癌细胞系肿瘤坏死因子耐药性的体外和体内研究 无胸腺小鼠的生物学行为。 4. 为了评估A20表达， 正常和恶性人乳腺组织标本以及正常和 恶性乳腺上皮细胞