Exploring the gain of function contribution of AKT to mammary tumorigenesis in mouse models.
Exploring the gain of function contribution of AKT to mammary tumorigenesis in mouse models.
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DOI：
10.1371/journal.pone.0009305
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发表时间：
2010-02-19
期刊：
影响因子：
3.7
通讯作者：
Carnero A
中科院分区：
文献类型：
--
作者：
Blanco-Aparicio C;Cañamero M;Cecilia Y;Pequeño B;Renner O;Ferrer I;Carnero A
在相当大比例的原发性人乳腺癌中已经注意到AKT的表达升高，这主要是由于PTEN/PI 3 K通路失调。为了研究乳腺肿瘤发生的功能依赖性机制中AKT获得的机制基础，我们以定量的方式探索了激活的AKT转基因诱导的表型。我们产生了几个转基因小鼠系表达不同水平的组成型活性AKT在乳腺。我们彻底分析了这些小鼠的癌前病变和肿瘤性乳腺病变，并将肿瘤发生过程与AKT水平相关联。最后，我们分析了一个可能的衰老检查点可能对观察到的肿瘤促进抑制的影响，将这些细胞系与乳腺特异性p53（R172 H）突变体表达和p27基因敲除小鼠交叉。我们通过病理学和分子水平分析参与PI 3 K/AKT通路和细胞衰老的蛋白质表达，广泛分析了良性、癌前病变和恶性病变。我们的研究结果表明，增加的癌前表型依赖于AKT信号，这是不改变p27或p53的损失。然而，通过R172 H点突变结合myrAKT转基因表达的p53失活显著增加了观察到的乳腺癌的百分比和大小，但不足以促进致瘤表型的完全消退。分子分析表明，来自双myrAKT;p53（R172 H）小鼠的肿瘤是由启动的p53（R172 H）肿瘤的加速引起的，而不是由AKT诱导的致癌衰老的旁路引起的。我们的工作表明，肿瘤不是衰老的旁路在MIN的后果。我们还表明，AKT诱导的致癌衰老是依赖于pRb，但不是p53。最后，我们的工作还表明，突变型p53和激活AKT之间观察到的合作是由于AKT诱导的突变型p53诱导的肿瘤的加速。最后，我们的工作表明，激活的AKT水平在良性或癌前病变的诱导中不是必需的，或者在AKT与其他致瘤信号如突变型p53的合作中，一旦AKT通路被激活，相对活性水平似乎不决定表型。
Elevated expression of AKT has been noted in a significant percentage of primary human breast cancers, mainly as a consequence of the PTEN/PI3K pathway deregulation. To investigate the mechanistic basis of the AKT gain of function-dependent mechanisms of breast tumorigenesis, we explored the phenotype induced by activated AKT transgenes in a quantitative manner. We generated several transgenic mice lines expressing different levels of constitutively active AKT in the mammary gland. We thoroughly analyzed the preneoplastic and neoplastic mammary lesions of these mice and correlated the process of tumorigenesis to AKT levels. Finally, we analyzed the impact that a possible senescent checkpoint might have in the tumor promotion inhibition observed, crossing these lines to mammary specific p53(R172H) mutant expression, and to p27 knock-out mice. We analyzed the benign, premalignant and malignant lesions extensively by pathology and at molecular level analysing the expression of proteins involved in the PI3K/AKT pathway and in cellular senescence. Our findings revealed an increased preneoplastic phenotype depending upon AKT signaling which was not altered by p27 or p53 loss. However, p53 inactivation by R172H point mutation combined with myrAKT transgenic expression significantly increased the percentage and size of mammary carcinoma observed, but was not sufficient to promote full penetrance of the tumorigenic phenotype. Molecular analysis suggest that tumors from double myrAKT;p53(R172H) mice result from acceleration of initiated p53(R172H) tumors and not from bypass of AKT-induced oncogenic senescence. Our work suggests that tumors are not the consequence of the bypass of senescence in MIN. We also show that AKT-induced oncogenic senescence is dependent of pRb but not of p53. Finally, our work also suggests that the cooperation observed between mutant p53 and activated AKT is due to AKT-induced acceleration of mutant p53-induced tumors. Finally, our work shows that levels of activated AKT are not essential in the induction of benign or premalignant tumors, or in the cooperation of AKT with other tumorigenic signal such as mutant p53, once AKT pathway is activated, the relative level of activity seems not to determine the phenotype.
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