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: 3916363
• 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/3916363
• 关键词: antiantibody; antireceptor antibody; benzanthracenes; binding proteins; breast neoplasms; chemical carcinogenesis; dexamethasone; epidermal growth factor; estrogens; gene expression; glucocorticoids; growth factor; human subject; laboratory mouse; laboratory rat; mammary epithelium; messenger RNA; mitogens; nitrosourea; nucleic acid hybridization; nucleic acid probes; nucleic acid sequence; oncogenes; point mutation; protooncogene; tissue /cell culture; transfection; transforming growth factors

Experiments are being conducted to determine the distribution and role of transforming growth factor alpha (TGFa ) in normal and malignant rodent and human mammary epithelial cells. Primary dimethylbenz (alpha) anthracene (DMBA) and nitrosomethylurea (NMU) induced rat mammary adenocarcinomas possess immunoreactive and biologically TGFalpha. A specific 4.8 Kb TGFalpha mRNA species could be detected in the DMBA - and NMU - induced rat mammary tumors. Ovariectomy produced a five to tenfold decrease in the expression of TGFa mRNA in the DMBA tumors. Nog 8 mouse mammary epithelial cells transfected with a plasmid containing a gluco- corticoid inducible MMTv-LTR linked to the point-mutated c-HA-ras proto-oncogene become transformed following the addition of dexamethesone (dex) to these cells. Following dex treatment, there is a rapid induction of the p21ras protein and of c-Ha-ras mRNA within 3 to 5 hours. During this interval there is a co- ordinate increase in the level of expression of TGFn mRNA and a subsequent increase in the production of TGFalpha protein. Human breast cancer cell lines are also producing TGFalpha and possess TGFalpha mRNA. In MCF-7 cells, the level of production of TGF alpha and TGF alpha mRNA expression can be enhanced by estrogens. 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 TGF alpha and TGF alpha mRNA can be detected in approximately 65% of primary human breast tumors. These results suggest that TGF alpha may function as an autocrine growth factor for a subset of rodent and human mammary tumor cells and that estrogens or activation or over- expression of a ras protooncogene may control the production of this growth factor.

正在进行实验，以确定分布和 转化生长因子α（TGF α）在正常和 恶性啮齿动物和人类乳腺上皮细胞。 初级 二甲基苯并蒽（DMBA）和亚硝基甲基脲（NMU） 诱导的大鼠乳腺癌具有免疫反应性， 生物学上的TGF α 一种特异的4.8 Kb TGF α mRNA种类 在DMBA和NMU诱导的大鼠乳腺癌模型中， 肿瘤的 卵巢切除术导致了五到十倍的 TGF α mRNA在DMBA肿瘤中的表达。 Nog 8小鼠乳房 用含有葡糖基葡糖苷酶的质粒转染的上皮细胞， 与点突变的c-HA-ras相关的皮质激素诱导的MMTv-LTR 原癌基因在加入 地塞米松（dex）对这些细胞。 在dex治疗后， 是p21ras蛋白和c-Ha-ras mRNA的快速诱导 在3到5小时内。 在这段时间里有一个坐标 TGFn mRNA表达水平的增加以及随后的 增加TGF α蛋白的产生。 人乳腺 癌细胞系也产生TGF α并拥有TGF α mRNA。 在MCF-7细胞中，TGF-α和TGF-β的产生水平与MCF-7细胞中的TGF-α和TGF-β的表达水平相关。 雌激素可增强α mRNA表达。 治疗 MCF-7细胞与多克隆抗人TGF α抗体或与 抗人EGF受体的单克隆抗体将抑制 这些细胞在体外的生长。 TGF α水平升高 TGF-α mRNA可以在大约65%的原发性 人类乳腺肿瘤 这些结果表明，TGF α可能 作为啮齿动物亚群自分泌生长因子发挥作用， 人乳腺肿瘤细胞与雌激素或激活或过度 ras原癌基因的表达可以控制 这个增长因素。