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）， 调蛋白（HRG）和cripto-1（CR-1）是结构上 在某些情况下，与表皮生长因子（EGF）功能相关 因为TGF-α和AR可以结合EGF受体（c-er B B），而 HRG与c-er B B-3或c-er B B-4结合。目前的研究有 证明MCF-10A人乳腺上皮细胞是 对外源性EGF、TGF-α或AR有丝分裂应答， 用点突变的c-Ha-ras转化这些细胞， 原癌基因导致内源性 TGF-α，AR和HRG，而这些细胞的erB B-2转化 导致AR和HRG表达上调。此外，委员会认为， 人TGF-α cDNA在这些细胞中的过表达导致其 体外转化加入抗EGF受体阻断剂 抗体抑制MCF-10A转化的乳腺细胞的生长 这表明在这些细胞中有一个外部自分泌环起作用。 雌激素可增加TGF-α和AR mRNA的表达， 在雌激素反应的人乳腺癌细胞系中的蛋白质。一 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 c-er B B-2、c-er B B-3或c-er B B-4 1型受体酪氨酸激酶 单独地或以各种异二聚体成对组合的形式。 然而，CR-1可以快速和短暂地增强酪氨酸激酶的活性。 磷酸化p46 Shc，并能激活MAPK亚型p42 erk 2。 125 I-CR-1结合135 kDa酪氨酸磷酸化的， 膜相关蛋白AR的蛋白和mRNA表达， CR-1已在约50%至80%的原发性和非原发性肿瘤中检测到， 转移性人类结直肠肿瘤，而只有5%的正常相邻 结肠或肝脏组织表达这些基因。同样，AR和CR-1也是 在大约80%的原发性人类乳腺肿瘤中检测到， 超过了邻近正常乳腺组织中的水平 上皮

Transforming growth factor alpha (TGF-alpha), amphiregulin (AR), 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 and AR can bind to the EGF receptor (c-erb B) whereas HRG binds to c-erb B-3 or c-erb B-4. The present studies have demonstrated that MCF-10A human mammary epithelial cells are mitogenically responsive to exogenous 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 TGF-alpha, AR and HRG whereas erb B-2 transformation of these cells results in an upregulation in 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.