Activation of Akt-1 (PKB-α) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion
Activation of Akt-1 (PKB-α) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion
复制标题
DOI：
10.1158/0008-5472.can-03-3465
复制
发表时间：
2004-05-01
期刊：
影响因子：
11.2
通讯作者：
Muller, WJ
中科院分区：
文献类型：
--
作者：
Hutchinson, JN;Jin, J;Muller, WJ
在相当大比例的原发性人类乳腺癌中，Akt-1 (PKBalpha) 的表达升高。人类乳腺癌发生中的另一个常见事件是 ErbB-2 受体酪氨酸激酶的扩增和过度表达，该事件与 Akt-1 的激活相关。为了直接评估 Akt-1 激活在 ErbB-2 乳腺肿瘤进展中的重要性，我们将携带小鼠乳腺肿瘤病毒/激活的 Akt-1 和小鼠乳腺肿瘤病毒/激活的 ErbB-2 的转基因小鼠的不同品系进行杂交，以获得在乳腺上皮中共表达转基因的后代。共表达激活的 Akt-1 和 ErbB-2 的雌性转基因小鼠会形成多灶性乳腺肿瘤，其潜伏期明显短于单独表达激活的 ErbB-2 的小鼠。乳腺肿瘤进展的急剧加速与细胞增殖增强、细胞周期蛋白 D1 蛋白水平升高以及视网膜母细胞瘤蛋白磷酸化相关。这些双转基因乳腺肿瘤还表现出对周围组织的较低水平的侵袭和更多分化的表型。与这些观察结果一致，共表达激活的 Akt-1 和 ErbB-2 的雌性小鼠比单独表达激活的 ErbB-2 菌株产生的转移灶明显更少。综上所述，这些观察结果表明，ErbB-2 诱导的乳腺肿瘤发生过程中 Akt-1 的激活可能对肿瘤生长和转移进展产生相反的影响。
Elevated expression of Akt-1 (PKBalpha) has been noted in a significant percentage of primary human breast cancers. Another frequent event in the genesis of human breast cancers is amplification and overexpression of the ErbB-2 receptor tyrosine kinase, an event which is associated with activation of Akt-1. To directly assess the importance of Akt-1 activation in ErbB-2 mammary tumor progression, we interbred separate strains of transgenic mice carrying mouse mammary tumor virus/activated Akt-1 and mouse mammary tumor virus/activated ErbB-2 to derive progeny that coexpress the transgenes in the mammary epithelium. Female transgenic mice coexpressing activated Akt-1 and ErbB-2 develop multifocal mammary tumors with a significantly shorter latency period than mice expressing activated ErbB-2 alone. This dramatic acceleration of mammary tumor progression correlates with enhanced cellular proliferation, elevated Cyclin D1 protein levels, and phosphorylation of retinoblastoma protein. These bitransgenic mammary tumors also exhibit lower levels of invasion into the surrounding tissue and more differentiated phenotypes. Consistent with these observations, female mice coexpressing activated Akt-1 and ErbB-2 developed significantly fewer metastatic lesions than the activated ErbB-2 strain alone. Taken together, these observations suggest that activation of Akt-1 during ErbB-2-induced mammary tumorigenesis may have opposing effects on tumor growth and metastatic progression.