ROLE OF TGFA IN THE ETIOLOGY AND PROGRESSION OF BREAST CANCER

TGFA 在乳腺癌病因和进展中的作用

• 批准号: 3813400
• 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/3813400
• 关键词: antiantibody; antireceptor antibody; benzanthracenes; breast neoplasms; chemical carcinogenesis; epidermal growth factor; estrogens; gene expression; growth factor receptors; growth inhibitors; human tissue; laboratory mouse; laboratory rat; mammary epithelium; messenger RNA; mitogens; monoclonal antibody; neoplasm /cancer genetics; neoplastic growth; nitrosourea; nucleic acid hybridization; nucleic acid probes; nucleic acid repetitive sequence; nucleic acid sequence; oncogenes; point mutation; protooncogene; tissue /cell culture; transfection; transforming growth factors

Transforming growth factor alpha (TGFalpha) has been circumstantially implicated in the autocrine growth of a number of different rodent and human tumor cells in vitro. However, its distribution and role in the etiology and/or progression of rodent and human breast cancer are relatively unknown. The present studies have demonstrated that biologically active and immunoreactive TGFalpha can be detected in hormone (estrogen)-dependent, DMBA- or NMU-induced rat mammary adenocarcinomas and that these tumors possess a specific 4.8-kb TGFalpha mRNA. These tumors also express elevated levels of c-Ha-ras protein (DMBA tumors) or possess a point-mutated c-Ha-ras gene (NMU tumors). Ovariectomy results in tumor regression and is preceded by a specific decrease in TGFA mRNA and protein. Transformation of nontransformed mouse mammary epithelial cell lines with a point-mutated c-Ha-ras protooncogene results in the loss in mitogenic responsiveness of these cells to exogenous epidermal growth factor (EGF) and a reduction in the number of unoccupied EGF receptors on these cells due in part to an enhanced production and secretion of TGFalpha. Several human breast cancer cell lines also secrete TGFalpha and possess TGFalpha mRNA. In the estrogen-responsive breast cancer cell lines, estrogen can induce a 3- to 5-fold increase in TGFalpha mRNA and protein. Treatment of these cells with a polyclonal anti-TGFalpha antibody or with a monoclonal anti-EGF receptor antibody can inhibit the growth of these cells in vitro. Elevated levels of TGFalpha protein or expression of TGFalpha mRNA can be detected in 50-60% of primary human breast tumors. No evidence was found for any gross amplifications and/or rearrangements of the TGFalpha gene in these tumors. Additionally, overexpression of a human TGFalpha gene in a cloned immortalized population of mouse and human mammary epithelial cells can lead to the malignant transformation of these cells in vitro and in vivo. Collectively, these results suggest that TGFalpha can function as an autocrine growth factor for a subset of rodent and human breast tumors, that estrogens or activated protooncogenes such as ras can enhance the expression of TGFalpha, and that enhanced production of TGFalpha can lead to the transformation of mammary epithelial cells that have a sufficient complement of functional EGF receptors.

转化生长因子α（TGF α）已被详细研究。 与许多不同啮齿动物的自分泌生长有关， 体外培养人肿瘤细胞。然而，它的分布和作用， 啮齿动物和人类乳腺癌病因学和/或进展是 相对未知。目前的研究表明，从生物学上讲， 在激素中可以检测到活性和免疫反应性TGF α， （雌激素）依赖性、DMBA或NMU诱导的大鼠乳腺腺癌和 这些肿瘤具有特定的4.8-kb TGF α mRNA。这些肿瘤 也表达高水平的c-Ha-ras蛋白（DMBA肿瘤）或具有 点突变的c-Ha-ras基因（NMU肿瘤）。卵巢切除导致肿瘤 消退，并且之前是TGFA mRNA和蛋白质的特异性降低。 用a转化未转化的小鼠乳腺上皮细胞系 点突变的c-Ha-ras原癌基因导致有丝分裂原的丧失 这些细胞对外源性表皮生长因子（EGF）的反应性 这些细胞上未被占用的EGF受体数量减少 部分原因是TGF α的产生和分泌增加。几 人乳腺癌细胞系也分泌TGF α并具有TGF α mRNA。在雌激素敏感的乳腺癌细胞系中，雌激素可以 诱导TGF α mRNA和蛋白质增加3 - 5倍。治疗 这些细胞与多克隆抗TGF α抗体或与单克隆 抗EGF受体抗体在体外可抑制这些细胞的生长。 TGF α蛋白水平升高或TGF α mRNA表达升高可导致 在50 - 60%的原发性人类乳腺肿瘤中检测到。没有发现任何证据 对于任何总体扩增和/或TGF α基因重排， 这些肿瘤。此外，在人TGF α基因的过度表达中， 小鼠和人乳腺上皮细胞的克隆永生化群体 可导致这些细胞在体外和体内的恶性转化。 vivo.总的来说，这些结果表明，TGF α可以作为一个功能， 自分泌生长因子用于啮齿动物和人类乳腺肿瘤的亚群， 雌激素或激活的原癌基因如ras可以增强 TGF α的表达，并且TGF α的产生增加可以导致 转化乳腺上皮细胞， EGF受体的功能。