Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression.
Akt1 and akt2 play distinct roles in the initiation and metastatic phases of mammary tumor progression.
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DOI：
10.1158/0008-5472.can-08-4287
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发表时间：
2009-06-15
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：
Dillon RL;Marcotte R;Hennessy BT;Woodgett JR;Mills GB;Muller WJ
PI 3 K/Akt存活通路在癌症中经常失调。我们以前的研究已经证明，活化的Akt 1与活化的ErbB 2或多瘤病毒中间T抗原（PyVm T Y315/322 F）从PI 3 K途径解偶联的共表达加速乳腺肿瘤的发展，但不能挽救与这些模型相关的转移表型。在这里，我们报告了在乳腺上皮中表达激活的Akt 2的转基因小鼠的产生。与MMTV-Akt 1株一样，Akt 2的乳腺特异性表达延迟了乳腺退化。然而，与Akt 1相反，在转基因小鼠乳腺中Akt 2与活化的ErbB 2或PyVmT Y315/322 F的共表达不影响肿瘤发展的潜伏期。引人注目的是，Akt 2共表达显著增加了两种肿瘤模型中肺转移的发生率，证明了在肿瘤进展中的独特作用。总之，这些观察结果表明，这些高度保守的激酶具有不同的生物和生化输出，在乳腺肿瘤诱导和转移中发挥相反的作用。
The PI3K/Akt survival pathway is often dysregulated in cancer. Our previous studies have demonstrated that coexpression of activated Akt1 with activated ErbB2 or polyoma virus middle T antigen uncoupled from the PI3K pathway (PyVmT Y315/322F) accelerates mammary tumor development but cannot rescue the metastatic phenotype associated with these models. Here we report the generation of transgenic mice expressing activated Akt2 in the mammary epithelium. Like the MMTV-Akt1 strain, mammary-specific expression of Akt2 delayed mammary gland involution. However, in contrast to Akt1, coexpression of Akt2 with activated ErbB2 or PyVmT Y315/322F in the mammary glands of transgenic mice did not impact the latency of tumor development. Strikingly Akt2 coexpresssion markedly increased the incidence of pulmonary metastases in both tumor models demonstrating a unique role in tumor progression. Together these observations argue that these highly conserved kinases have distinct biological and biochemical outputs that play opposing roles in mammary tumor induction and metastasis.