ROLE OF EGF-RELATED PEPTIDES IN THE PATHOGENESIS OF BREAST AND COLON CANCER

转化生长因子α（TGF-α），双调蛋白（AR）， 肝素结合生长因子（HB-EGF）、调蛋白（HRG）和cripto-1 （CR-1）是在结构上并且在某些情况下在功能上与CR1结合的蛋白质。 与表皮生长因子（EGF）相关的TGF-α，HB-EGF和 AR可结合EGF受体（c-erB B），而HRG结合c-erbB-3 或c-er B B-4。目前的研究表明，MCF-10A人 乳腺上皮细胞对外源EGF有丝分裂反应， HB-EGF、TGF-α或AR的转化，以及用 点突变的c-Ha-ras原癌基因导致 内源性HB-EGF、TGF-α、AR和HRG的表达，而erB B-2的表达 这些细胞的转化仅导致AR的上调， HRG表达。此外，人TGF-α cDNA的过表达 导致它们在体外转化。添加 抗EGF受体阻断抗体抑制MCF-10A的生长 转化的乳腺细胞，这表明外部自分泌回路是 在这些细胞中工作。雌激素可增加TGF-β 1的表达， 雌激素敏感性乳腺癌中α和AR mRNA和蛋白的表达 细胞系重组CR-1蛋白能够适度刺激 小鼠和人乳腺上皮细胞的增殖， 抑制β-酪蛋白和乳清酸性蛋白表达。CR-1不 EGF受体不能直接激活EGF受体。 er B B-2、c-er B B-3或c-er B B-4 1型受体酪氨酸激酶， 单独或以各种异二聚体成对组合的形式。然而，在这方面， CR-1能迅速、短暂地增强酪氨酸磷酸化 并能激活MAPK亚型p42erk2。125I-CR-1结合 135 kDa酪氨酸磷酸化和膜相关蛋白。 AR和CR-1的蛋白质和mRNA表达已被检测到， 约50%至80%的原发性和转移性人类结直肠癌 肿瘤，而只有5%的正常邻近结肠或肝脏组织表达 这些基因。同样，在大约80%的人中检测到AR和CR-1。 原发性人类乳腺肿瘤的水平超过了 邻近正常乳腺上皮。

Transforming growth factor alpha (TGF-alpha), amphiregulin (AR), heparin-binding growth factor (HB-EGF), heregulin (HRG) and cripto-1 (CR-1) are proteins that are structurally and in some cases functionally related to epidermal growth factor (EGF) in that TGF-alpha, HB-EGF and AR can bind to the EGF receptor (c-erb B) whereas HRG binds to c-erbB-3 or c-erb B-4. The present studies have demonstrated that MCF-10A human mammary epithelial cells are mitogenically responsive to exogenous EGF, HB-EGF, TGF-alpha or AR and that transformation of these cells with a point-mutated c-Ha-ras protooncogene results in an increase in the expression of endogenous HB-EGF, TGF-alpha, AR and HRG whereas erb B-2 transformation of these cells results in an upregulation in only AR and HRG expression. Furthermore, overexpression of a human TGF-alpha cDNA in these cells leads to their in vitro transformation. Addition of an anti-EGF receptor blocking antibody inhibits the growth of MCF-10A transformed mammary cells suggesting that an external autocrine loop is operative in these cells. Estrogens can increase the expression of TGF- alpha and AR mRNA and protein in estrogen-responsive human breast cancer cell lines. A recombinant CR-1 protein is able to moderately stimulate the proliferation of mouse and human mammary epithelial cells and to inhibit beta-casein and whey acidic protein expression. CR-1 does not directly bind to the EGF receptor nor does it directly activate the c- erb B-2, c-erb B-3 or c-erb B-4 type 1 receptor tyrosine kinases either singularly or in various heterodimeric pairwise combinations. However, CR-1 can rapidly and transiently enhance the tyrosine phosphorylation of p46 Shc and can activate the MAPK isoform, p42erk2. 125I-CR-1 binds to a 135 kDa tyrosine phosphorylated and membrane-associated protein. Protein and mRNA expression for AR and CR-1 have been detected in approximately 50% to 80% of primary and metastatic human colorectal tumors, whereas only 5% of normal adjacent colon or liver tissue express these genes. Likewise,AR and CR-1 were detected in approximately 80% of primary human breast tumors at a level that exceeded the level found in adjacent normal normal mammary epithelium.