ALPHA TRANSFORMING GROWTH FACTORS IN RODENT AND HUMAN MAMMARY CARCINOMAS

啮齿动物和人类乳腺癌中的 ALPHA 转化生长因子

• 批准号: 3939333
• 负责人: D S SALOMON
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3939333
• 关键词: benzanthracenes; breast neoplasms; chemical carcinogenesis; clone cells; complementary DNA; electrofocusing; epidermal growth factor; estrogen inhibitor; estrogens; fibroblasts; gene expression; growth factor; high performance liquid chromatography; human milk; human tissue; mammary epithelium; nitrosourea; oncogenes; tissue /cell culture; transforming growth factors

Experiments are being conducted to determine the distribution and role of alpha transforming growth factors (alpha TGFs) in normal and malignant rodent and human mammary epithelial cells. Primary dimethylbenz (alpha) anthracene (DMBA) and nitrosomethylurea (NMU) rat mammary adenocarcinomas possess three to seven-fold more biologically active and immunoreactive alpha TGFs than transplantable DMBA-I and NMU-II carcinomas. Moreover, a specific 5.0 kb mRNA species could be detected in the primary DMBA and NMU tumors following hybridization of poly A(+) RNA to a human and mouse alpha TGF cDNA probes but not in the DMBA-I or NMU-II tumors. Ovariectomy produced a two to three-fold decrease in the level of alpha TGFs in the primary DMBA tumors which was preceeded by a loss in the expression of alpha TGF mRNA. Mouse mammary epithelial which have been transformed with a point-mutated c-Ha-ras proto-oncogene, NMuMG/rasH cells, become resistant to the growth promoting effects of EGF because these cells have an increased capacity to synthesize alpha TGF mRNA. Human breast cancer cell lines are also producing alpha TGF and possess alpha TGF mRNA. In MCF-7 cells, the level of production of alpha TGF and TGF alpha mRNA expression can be enhanced by estrogens and blocked by anti-estrogens. In addition treatment of MCF-7 cells with a polyclonal anti-human TGF alpha antibody or with a monoclonal antibody against the human EGF receptor will inhibit the growth of these cells in vitro. Elevated levels of immunoreactive alpha TGF and alpha TGF mRNA can be detected in approximately 65% of primary human breast carcinomas. These is a strong positive correlation between the presence of alpha TGF mRNA and the presence of functional estrogen receptors in a subset of these tumors. These results suggest that TGF alpha may function as an autocrine growth factor for a subset of rodent and human mammary tumor cells which are estrogen responsive and that the activation or overexpression of a ras proto-oncogene may also control the level of TGF alpha production.

正在进行实验，以确定分布情况 和α转化生长因子(αTGFs)在血管内皮细胞中的作用 正常和恶性啮齿动物与人乳腺上皮 细胞。伯二甲基苯(α)菲(DMBA)和 亚硝基甲基脲(NMU)大鼠乳腺腺癌 生物活性和免疫反应性提高三到七倍 与可移植的DMBA-I和NMU-II癌相比，α-TGFs的作用更强。 此外，还可以检测到特定的5.0kb的mrna物种。 原位杂交后的DMBA和NMU肿瘤 Poly A(+)RNA对人和小鼠α-转化生长因子的cDNAs探针 在DMBA-I或NMU-II肿瘤中不存在。卵巢切除产生了一种 阿尔法转化生长因子水平下降两到三倍 原发性DMBA肿瘤，在此之前发生了 α-转化生长因子基因的表达。小鼠乳腺上皮细胞 已经用点突变的c-Ha-ras进行了转化 原癌基因NMuMG/Rash细胞对 EGF的促生长作用是因为这些细胞具有 增加合成α-转化生长因子基因的能力。人类 乳腺癌细胞株也产生α-转化生长因子，并拥有 α-转化生长因子基因。在MCF-7细胞中，产生的水平 α-转化生长因子和转化生长因子-α基因的表达 雌激素，并被抗雌激素阻断。此外，还应对 抗人转化生长因子α多克隆抗体诱导的MCF-7细胞 用抗人表皮生长因子受体的单抗 在体外抑制这些细胞的生长。高水平的 可检测到免疫阳性的α-转化生长因子和α-转化生长因子mRNA 在大约65%的原发人类乳腺癌中。 这是一个很强的正相关关系 α-转化生长因子基因与功能性雌激素的存在 这些肿瘤的一个子集中的受体。这些结果表明， 转化生长因子α可能作为一种自分泌生长因子作用于 啮齿动物和人类乳腺肿瘤细胞亚群 雌激素反应，激活或过度表达一种 RAS原癌基因也可能控制转化生长因子α的水平 制作。