ROLE OF TGFA IN THE ETIOLOGY AND PROGRESSION OF BREAST CANCER

转化生长因子α(TGFα)已被间接证实 与许多不同啮齿动物的自分泌生长有关 体外培养的人肿瘤细胞。然而，它在地球上的分布和作用 啮齿动物和人类乳腺癌的病因和/或进展是 相对不为人所知。目前的研究已经从生物学上证明了 在激素中可检测到活性和免疫反应的TGFα (雌激素)依赖、DMBA或NMU诱导的大鼠乳腺癌和 这些肿瘤具有4.8kb的特异性TGFpha mRNA。这些肿瘤 也表达c-Ha-ras蛋白水平升高(DMBA肿瘤)或具有 点突变c-Ha-ras基因(NMU肿瘤)。卵巢切除导致肿瘤 在此之前，TGFA的mRNA和蛋白出现了特异性的下降。 A对未转化小鼠乳腺上皮细胞系的转化作用 C-Ha-ras原癌基因点突变导致有丝分裂原基因缺失 这些细胞对外源性表皮生长因子的反应性 这些细胞上未被占用的EGF受体的数量减少 部分原因是增加了转化生长因子α的产生和分泌。几个 人乳腺癌细胞株也分泌TGFα，并拥有TGFAlpha MRNA.在对雌激素敏感的乳腺癌细胞系中，雌激素可以 诱导转化生长因子α基因和蛋白表达增加3-5倍。治疗 这些细胞用多克隆抗TGFα抗体或用单克隆化 抗EGF受体抗体在体外可抑制这些细胞的生长。 转化生长因子α蛋白水平或转化生长因子αmRNA的表达升高可能是 在50%-60%的原发人类乳腺肿瘤中检测到。没有找到任何证据 对于转化生长因子α基因的任何粗略扩增和/或重排 这些肿瘤。此外，人转化生长因子α基因在小鼠体内过表达 克隆的小鼠和人乳腺上皮细胞永生化群体 可导致这些细胞在体外和在 活着。总而言之，这些结果表明，TGFα可以作为一种 啮齿动物和人类乳腺肿瘤亚群的自分泌生长因子， 雌激素或激活的原癌基因，如ras，可以增强 表达转化生长因子α，且促进转化生长因子α产生可导致 对乳腺上皮细胞的转化有足够的 功能性EGF受体的补充。

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.