von Lintig F C, Dreilinger A D, Varki N M, Wallace A M, Casteel D E, Boss G R
Department of Medicine, and Cancer Center, University of California, San Diego, La Jolla, USA.
Breast Cancer Res Treat. 2000 Jul;62(1):51-62. doi: 10.1023/a:1006491619920.
Genetic ras mutations are infrequent in breast cancer but Ras may be pathologically activated in breast cancer by overexpression of growth factor receptors which signal through Ras. Using a highly sensitive, coupled enzymatic assay, we measured Ras activation in 20 breast cancers, two fibroadenomas, and seven normal breast samples. Ras was highly activated compared to benign tissue in 11 of the 20 cancers; 7 of these 11 cancers expressed both the epidermal growth factor (EGF) and ErbB-2/neu/HER-2 receptors with the remaining four cancers with high Ras activation expressing one of these two receptors. In the other nine cancers, Ras activation was similar to that observed in benign breast tissue with none of these cancers expressing the EGF receptor while one expressed the ErbB-2 receptor. None of the cancers tested had an activating K-ras mutation nor did any of the cancers express a truncated EGF receptor or the c-FMS receptor. The activity of mitogen-activated protein (MAP) kinase was high in the cancers, and reflected the degree of Ras activation. In cultured mammary tumor cell lines, we showed that Ras activation was ligand dependent in cells overexpressing the ErbB-2 receptor. Thus, Ras was abnormally activated in breast cancers overexpressing the EGF and/or ErbB-2 receptors indicating there are sufficient ligands in vivo to activate these receptors, and this work provides a basis for new target-based treatments of this disease.
在乳腺癌中，ras基因的突变并不常见，但生长因子受体的过表达可通过Ras信号通路在病理上激活Ras，从而引发乳腺癌。我们采用一种高灵敏度的偶联酶分析法，检测了20例乳腺癌、2例纤维腺瘤和7例正常乳腺样本中的Ras激活情况。与良性组织相比，20例癌症中有11例的Ras被高度激活；这11例癌症中有7例同时表达表皮生长因子（EGF）和ErbB-2/neu/HER-2受体，其余4例Ras高度激活的癌症则表达这两种受体中的一种。在其他9例癌症中，Ras激活情况与良性乳腺组织相似，这些癌症均未表达EGF受体，仅有1例表达ErbB-2受体。所检测的癌症均未发生激活型K-ras突变，也没有任何癌症表达截短型EGF受体或c-FMS受体。丝裂原活化蛋白（MAP）激酶的活性在癌症中较高，且反映了Ras激活的程度。在培养的乳腺肿瘤细胞系中，我们发现，在过表达ErbB-2受体的细胞中，Ras激活是依赖配体的。因此，在过表达EGF和/或ErbB-2受体的乳腺癌中，Ras被异常激活，这表明体内存在足够的配体来激活这些受体，这项研究为基于新靶点的该疾病治疗提供了依据。
