EGF-RELATED PEPTIDES IN THE ETIOLOGY AND PROGRESSION OF BREAST AND COLON CANCER

乳腺癌和结肠癌的病因和进展中的 EGF 相关肽

• 批准号: 3796501
• 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/3796501
• 关键词: MCF7 cell; antireceptor antibody; blocking antibody; breast neoplasms; cell growth regulation; colorectal neoplasms; epidermal growth factor; estrogens; gene expression; genetic promoter element; growth factor receptors; hormone related neoplasm /cancer; human tissue; molecular oncology; neoplastic growth; neoplastic transformation; neutralizing antibody; oncogenes; protooncogene; reporter genes; transfection; transforming growth factors

Transforming growth factor alpha (TGFalpha), amphiregulin (AR) and cripto are proteins that are structurally and in some cases functionally related to epidermal growth factor (EGF) in that TGFalpha and AR can bind to the EGF receptor. TGFalpha has been implicated in the autocrine growth of a number of different human carcinoma cells such as breast and colon tumors. However, the regulation of expression of TGFalpha and interference with its biological activity have not been thoroughly examined; and relative levels of expression and biological function of AR and cripto in these malignancies are unknown. Present studies demonstrate that transformation of human mammary epithelial cells with a point-mutated c-Ha-ras protooncogene, but not with a c-erbB-2 oncogene, results in an increase in TGFalpha expression. Also, overexpression of human TGFalpha cDNA in these cells leads to in vitro transformation. Addition of an anti-EGF receptor blocking antibody or an anti-TGFalpha neutralizing antibody can partially or completely inhibit the growth of the ras or TGFalpha transformed mammary cells, suggesting the establishment of an external autocrine loop. Estrogens can increase TGFalpha mRNA and protein expression in estrogen-responsive human breast cancer cell lines like MCF-7 cells. Transient transfection assays in MCF-7 cells using a plasmid containing the TGFalpha promoter ligated to either the chloramphenicol acetyltransferase (CAT) or luciferase genes demonstrate that physiological concentrations of estrogens can induce a 10-to 100-fold increase in the activity of these reporter genes. This suggests that the TGFalpha promoter contains a cis-acting estrogen-responsive element (ERE) MCF-7 cells were infected with a recombinant amphotropic TGFalpha antisense expression vector. Expression of this antisense RNA leads to partial reduction in basal and estrogen-induced TGFalpha protein production and to an equivalent degree of inhibition of basal and estrogen-induced proliferation. Specific mRNA transcripts for AR and cripto were detected in approximately 70% of primary and metastatic colorectal tumors, but only 5% of normal colon or liver tissue expressed these genes. In contrast, cripto mRNA was not expressed in either normal or malignant human mammary tissue whereas AR mRNA was found in approximately 50% of these samples.

转化生长因子α（TGF α）、双调蛋白（AR）和cripto 是在结构上和某些情况下在功能上 表皮生长因子（EGF），因为TGF α和AR可以结合到 EGF受体 TGF-α与肿瘤细胞的自分泌生长有关， 许多不同的人类癌细胞，如乳腺癌和结肠癌 肿瘤的 然而，TGF α和TGF β 1表达的调节 干扰其生物活性， 检查;和AR的相对表达水平和生物学功能 和cripto在这些恶性肿瘤中是未知的。 本研究 证明了人乳腺上皮细胞的转化具有 点突变的c-Ha-ras原癌基因，但不含c-erbB-2癌基因， 导致TGF α表达增加。 此外，过度表达 这些细胞中的人TGF α cDNA导致体外转化。 添加抗EGF受体阻断抗体或抗TGF α 中和抗体可以部分或完全抑制 ras或TGF α转化的乳腺细胞，表明 建立外部自分泌回路。 雌激素可以增加 雌激素反应性乳腺组织中TGF α mRNA和蛋白的表达 癌细胞系如MCF-7细胞。 瞬时转染试验 MCF-7细胞，使用含有连接至 氯霉素乙酰转移酶（CAT）或荧光素酶基因 表明生理浓度的雌激素可以诱导 这些报告基因的活性增加了10到100倍。 这 表明TGF α启动子含有顺式作用的 雌激素反应元件（ERE）MCF-7细胞感染一种 重组嗜酸性TGF α反义表达载体。 表达 这种反义RNA的部分减少导致基础和 雌激素诱导的TGF α蛋白的产生， 抑制基础和雌激素诱导的增殖。 特异性mRNA 在大约70%的人中检测到AR和cripto的转录本。 原发性和转移性结直肠肿瘤，但只有5%的正常结肠或 肝组织表达这些基因。 相比之下，cripto mRNA没有 在正常或恶性人乳腺组织中表达，而AR 在这些样品中发现约50%的mRNA。