Amundadottir L T, Leder P
Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.
Oncogene. 1998 Feb 12;16(6):737-46. doi: 10.1038/sj.onc.1201829.
We have assessed five signal transduction pathways to determine the role each might play in the malignant transformation of mammary epithelium initiated by neu, heregulin/NDF, TGFalpha, v-Ha-ras and c-myc in transgenic mice. The study involves a molecular and pharmacologic assessment of Erk/MAP kinase, Jnk/SAP kinase, PI 3-kinase, protein kinase C, and the Src-related kinases Lck and Fyn. Our results indicate that oncogenes capable of transforming mammary gland epithelium activate and require specific signal transduction pathways. For example, mammary tumors initiated by neu, v-Ha-ras and c-myc have high levels of active Erk/MAP kinase and their anchorage independent growth is strongly inhibited by PD098059, an inhibitor of Mek/ MAP kinase kinase. By contrast, Erk/MAP kinase activity is weak in tumors initiated by TFGalpha and heregulin/NDF and the corresponding cell lines are not growth inhibited by PD098059. Similarly, PI 3-kinase is strongly activated in neu, TGFalpha and heregulin/NDF initiated tumor cell lines, but not in c-myc or v-Ha-ras initiated tumor cell lines. The anchorage independent growth of all these tumor cell lines are, however, inhibited by the specific PI 3-kinase inhibitor LY294001. Further illustrating this oncogene-based specificity, PP1, a specific inhibitor of the Src-like kinases, Lck and Fyn, blocks anchorage-independent cell growth only in the TGFalpha initiated mammary tumor cell line. Taken together with additional observations, we conclude that certain oncogenes reliably require the recruitment/activation of specific signal transduction pathways. Such specific relationships between the initiating oncogene and a required pathway may reflect a direct activating effect or the parallel activation of a pathway that is a necessary oncogenic collaborator for transformation in the mammary gland. The work points to a molecular basis for targeting therapy when an initiating oncogene can be implicated; for example, because of amplification, increased expression, genetic alteration, or heritable characteristics.
我们评估了五条信号转导通路，以确定它们在由neu、神经调节蛋白/神经分化因子（heregulin/NDF）、转化生长因子α（TGFalpha）、v-Ha-ras和c-myc引发的转基因小鼠乳腺上皮恶性转化过程中可能发挥的作用。该研究涉及对细胞外调节蛋白激酶/丝裂原活化蛋白激酶（Erk/MAP kinase）、应激活化蛋白激酶（Jnk/SAP kinase）、磷脂酰肌醇-3激酶（PI 3-kinase）、蛋白激酶C以及与Src相关的激酶Lck和Fyn进行分子和药理学评估。我们的结果表明，能够转化乳腺上皮的癌基因会激活并需要特定的信号转导通路。例如，由neu、v-Ha-ras和c-myc引发的乳腺肿瘤具有高水平的活性Erk/MAP激酶，其不依赖贴壁生长受到PD098059（一种Mek/ MAP激酶激酶抑制剂）的强烈抑制。相比之下，在由转化生长因子α（TFGalpha）和神经调节蛋白/神经分化因子（heregulin/NDF）引发的肿瘤中，Erk/MAP激酶活性较弱，相应的细胞系不受PD098059的生长抑制。同样，PI 3-激酶在由neu、转化生长因子α（TGFalpha）和神经调节蛋白/神经分化因子（heregulin/NDF）引发的肿瘤细胞系中被强烈激活，但在由c-myc或v-Ha-ras引发的肿瘤细胞系中未被激活。然而，所有这些肿瘤细胞系的不依赖贴壁生长都受到特异性PI 3-激酶抑制剂LY294001的抑制。Src样激酶Lck和Fyn的特异性抑制剂PP1仅在由转化生长因子α（TGFalpha）引发的乳腺肿瘤细胞系中阻断不依赖贴壁的细胞生长，这进一步说明了这种基于癌基因的特异性。结合其他观察结果，我们得出结论，某些癌基因确实需要募集/激活特定的信号转导通路。起始癌基因与所需通路之间的这种特定关系可能反映了一种直接激活作用，或者是一条对于乳腺转化而言是必要致癌协同因子的通路的平行激活。这项工作指出了在确定起始癌基因时进行靶向治疗的分子基础；例如，由于扩增、表达增加、基因改变或遗传特征。
