Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes
Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes
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DOI：
10.1038/sj.onc.1201829
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发表时间：
1998-02-12
期刊：
影响因子：
8
通讯作者：
Leder, P
中科院分区：
文献类型：
--
作者：
Amundadottir, LT;Leder, P
我们已经评估了五种信号转导途径，以确定每种途径在转基因小鼠中由neu、heregulin/NDF、TGF α、v-Ha-ras和c-myc引发的乳腺上皮恶性转化中可能发挥的作用。该研究涉及Erk/MAP激酶、JNk/SAP激酶、PI 3-激酶、蛋白激酶C以及Src相关激酶Lck和Fyn的分子和药理学评估，我们的研究结果表明，能够转化乳腺上皮的癌基因激活并需要特定的信号传导途径，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，并且其锚定非依赖性生长被Mek/ MAP激酶抑制剂PD 098059强烈抑制，相比之下，Erk/MAP I;激酶活性在由TI引发的肿瘤中较弱;TFG α和heregulin/NDF以及相应的细胞系不受PD 098059的生长抑制。和heregulin/NDF启动的肿瘤细胞系，但在c-myc或v-Ha-rns启动的肿瘤细胞系中没有。然而，所有这些肿瘤细胞系的锚定非依赖性生长都被特异性PI 3激酶抑制剂LY 294001抑制。进一步说明这种基于癌基因的特异性，PP 1，Src样激酶Lck和Fyn的特异性抑制剂，仅在TGF α中阻断锚定非依赖性细胞生长; CL启动的乳腺肿瘤细胞系，结合额外的观察，我们得出结论，某些癌基因可靠地需要特定信号转导途径的募集/激活，起始致癌基因和所需途径之间的这种特定关系可能反映了作为乳腺转化所必需的致癌协作者的途径的直接激活效应或平行激活，这项工作为靶向治疗提供了分子基础，例如，由于扩增、表达增加、遗传改变或遗传特征，可能涉及起始癌基因。
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, TGF alpha, 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 as 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 I;kinase activity is weak in tumors initiated by TI;TFG alpha and heregulin/NDF and the corresponding cell lines are not growth inhibited by PD098059, Similarly, PI 3-kinase is strongly activated in neu, TGF alpha;! and heregulin/NDF initiated tumor cell lines, but not in c-myc or v-Ha-rns 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 TGF alpha;cl 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.