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

EGF 相关肽在乳腺癌和结肠癌发病机制中的作用

• 批准号: 6289225
• 负责人: DAVID SALOMON
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/6289225
• 关键词: antireceptor antibody; autocrine; blocking antibody; breast neoplasms; cell growth regulation; colon neoplasms; epidermal growth factor; estrogens; gene expression; growth factor receptors; hormone regulation /control mechanism; human tissue; mammary epithelium; neoplastic process; neoplastic transformation; protein tyrosine kinase; protooncogene; receptor binding; tissue /cell culture; transforming growth factors

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,

转化生长因子α (TGF- α)、双调节蛋白（AR）、肝素结合生长因子（HB-EGF）、heregulin （HRG）和cripto-1 （CR-1）是在结构上和某些情况下在功能上与表皮生长因子（EGF）相关的蛋白质，其中TGF- α、HB-EGF和AR可以与表皮生长因子受体（c- erbb B）结合，而HRG则与c-erbB-3或c- erbb -4结合。目前的研究表明，MCF-10A人乳腺上皮细胞对外源性EGF、HB-EGF、tgf - α或AR有丝分裂反应，这些细胞与点突变的c-Ha-ras原癌基因的转化导致内源性HB-EGF、tgf - α、AR和HRG的表达增加，而这些细胞的erbb -2转化只导致AR和HRG的表达上调。此外，人tgf - α cDNA在这些细胞中的过表达导致它们在体外转化。添加抗egf受体阻断抗体可抑制MCF-10A转化的乳腺细胞的生长，这表明这些细胞中存在外部自分泌环。雌激素可增加雌激素应答的人乳腺癌细胞株中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，抑制β -酪蛋白和乳清酸性蛋白的表达。此外，CR-1在体外和体内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还可以通过caspase-3依赖性途径诱导乳腺上皮细胞亚群的凋亡。最后，CR-1可以通过基质或1型胶原包被过滤器刺激趋化作用和小鼠乳腺上皮细胞的侵袭。CR-1不直接与EGF受体结合，也不直接激活c- erbb -2、c- erbb -3或c- erbb -4型1受体酪氨酸激酶，无论是单一的还是以各种异源二聚体成对组合。然而，CR-1可以快速、短暂地增强p46 Shc的酪氨酸磷酸化，并激活MAPK的异构体p42erk2。125125I-CR-1可以特异性交联到130 kDa和60 kDa的蛋白，这与其他草本b相关的酪氨酸激酶不同。虽然CR-1不能直接结合四种已知的erb酪氨酸激酶受体，但它可以特异性地增强erb -4的间接酪氨酸磷酸化。动词B-4的表达或活性的减少显著损害了CR-1激活MAPK的能力。在大约50%至80%的原发性和转移性人类结直肠肿瘤中检测到AR和CR-1的mRNA表达，而只有5%的正常邻近结肠或肝组织表达这些基因。同样，在大约80%的原发人乳腺肿瘤中检测到AR和CR-1，其水平超过了邻近正常乳腺上皮的水平。-乳腺癌，crypto， EGF，生长因子，TGF，