THE 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）是在结构上和在某些情况下在功能上与表皮生长因子（EGF）相关的蛋白质，因为TGF-α、HB-EGF和AR可以结合EGF受体（c-erB B），而HRG结合c-erB-3或c-erB B-4。目前的研究表明，MCF-10 A人乳腺上皮细胞对外源性EGF、HB-EGF、TGF-α或AR有促有丝分裂反应，并且用点突变的c-Ha-ras原癌基因转化这些细胞导致内源性HB-EGF、TGF-α、AR和HRG表达增加，而这些细胞的erB B-2转化仅导致AR和HRG表达上调。此外，人TGF-α cDNA在这些细胞中的过表达导致它们的体外转化。添加抗EGF受体阻断抗体抑制MCF-10A转化的乳腺细胞的生长，表明外部自分泌回路在这些细胞中起作用。雌激素可增加雌激素敏感的人乳腺癌细胞系中TGF-α和AR mRNA及蛋白的表达。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，并抑制β-酪蛋白和乳清酸性蛋白的表达。此外，CR-1在体内外均能刺激小鼠乳腺上皮细胞的分支形态发生，我们最近发现CR-1还能通过caspase-3依赖的途径诱导乳腺上皮细胞亚群的凋亡。最后，CR-1可以通过基质胶或1型胶原包被的过滤器刺激小鼠乳腺上皮细胞的趋化和侵袭。CR-1不直接结合EGF受体，也不直接激活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，无论是单独激活还是以各种异二聚体成对组合激活。然而，CR-1可以快速和短暂地增强p46 Shc的酪氨酸磷酸化，并可以激活MAPK亚型p42 erk 2。125125 I-CR-1可特异性交联至与其它erb B相关酪氨酸激酶不同的130 kDa和60 kDa蛋白。尽管CR-1不能直接结合四种已知的er B酪氨酸激酶受体中的任何一种，但它可以特异性地增强er B B-4的间接酪氨酸磷酸化。erB B-4表达或活性的消除显著损害CR-1激活MAPK的能力。AR和CR-1的mRNA表达已在约50%至80%的原发性和转移性人类结直肠肿瘤中检测到，而仅5%的正常邻近结肠或肝组织表达这些基因。同样，在约80%的原发性人乳腺肿瘤中检测到AR和CR-1，其水平超过了在相邻正常乳腺上皮中发现的水平。- 乳腺癌，Cripto，EGF，生长因子，TGF，

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. In addition, CR-1 can stimulate branching morphogenesis of mouse mammary epithelial cells in vitro and in vivo.We have recently found that CR-1 can also induce apoptosis in a subpopulation of mammary epithelial cells through a caspase-3-dependent pathway. Finally, CR-1 can stimulate chemotaxsis and the invasion of mouse mammary epithelial cells through matrigel or type-1 collagen-coated filters. 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. 125125I-CR-1 can be specifically cross-linked to a 130 kDa and a 60 kDa protein that are distinct from other erb B-related tyrosine kinases. Although CR-1 fails to directly bind to any of the four known erb tyrosine kinase receptors, it can specifically enhance the indirect tyrosine phosphorylation of erb B-4. Abrogation of erb B-4 expression or activity significantly impairs the ability of CR-1 to activate MAPK. 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. - breast cancer, Cripto, EGF, growth factors, TGF,