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: 3808554
• 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/3808554
• 关键词: antiantibody; antireceptor antibody; blocking antibody; breast neoplasms; colorectal neoplasms; epidermal growth factor; estrogens; gene expression; genetic promoter element; genetic regulatory element; genetic transcription; growth factor receptors; growth inhibitors; human tissue; mammary epithelium; messenger RNA; metastasis; monoclonal antibody; neoplasm /cancer genetics; neoplastic growth; neutralizing antibody; oncogenes; protooncogene; tissue /cell culture; transfection; transforming growth factors

Transforming growth factor a (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 clement (ERE) MCF-7 cells were infected with a recom- binant 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 a (TGFalpha)、双调蛋白 (AR) 和 cripto 是结构相关且在某些情况下功能相关的蛋白质 表皮生长因子（EGF），因为 TGFα 和 AR 可以结合 EGF受体。 TGFα 与自分泌生长有关 不同人类癌细胞的数量，例如乳腺癌和结肠癌 肿瘤。 然而，TGFα 的表达调节和 对其生物活性的干扰尚未彻底解决 检查； AR的表达和生物学功能的相对水平 而 cripto 在这些恶性肿瘤中的作用尚不清楚。 目前的研究 证明人乳腺上皮细胞的转化 点突变的 c-Ha-ras 原癌基因，但不带有 c-erbB-2 癌基因， 导致 TGFα 表达增加。 另外，过度表达 这些细胞中的人 TGFα cDNA 导致体外转化。 添加抗 EGF 受体阻断抗体或抗 TGFα 中和抗体可以部分或完全抑制生长 ras 或 TGFalpha 转化的乳腺细胞，表明 建立外部自分泌环路。 雌激素可以增加 雌激素反应性人乳腺中 TGFα mRNA 和蛋白的表达 癌细胞系，如 MCF-7 细胞。 瞬时转染测定 MCF-7 细胞使用含有 TGFalpha 启动子的质粒连接 氯霉素乙酰转移酶 (CAT) 或荧光素酶基因 证明生理浓度的雌激素可以诱导 这些报告基因的活性增加 10 至 100 倍。 这 表明 TGFα 启动子含有顺式作用 雌激素反应细胞（ERE）MCF-7细胞被感染 双性双嗜性TGFα反义表达载体。 表达 这种反义RNA导致基础和 雌激素诱导的 TGFα 蛋白产生并达到同等程度 抑制基础增殖和雌激素诱导的增殖。 特异性mRNA 大约 70% 的人中检测到了 AR 和 cripto 的转录本 原发性和转移性结直肠肿瘤，但仅占正常结肠的 5% 或 肝脏组织表达这些基因。 相比之下，cripto mRNA 则没有 在正常或恶性人类乳腺组织中表达，而 AR 大约 50% 的样本中发现了 mRNA。