Oncogenic AKT1(E17K) mutation induces mammary hyperplasia but prevents HER2-driven tumorigenesis.
Oncogenic AKT1(E17K) mutation induces mammary hyperplasia but prevents HER2-driven tumorigenesis.
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DOI：
10.18632/oncotarget.8191
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发表时间：
2016-04-05
期刊：
影响因子：
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通讯作者：
Toker A
中科院分区：
文献类型：
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作者：
Mancini ML;Lien EC;Toker A
在乳腺癌中最常失调的信号传导途径之一是PI 3-K/Akt级联。遗传病变通常存在于PIK 3CA、PTEN和AKT中，其导致Akt和下游信号传导的过度和组成性激活，导致不受控制的增殖和增加的细胞存活。一种这样的遗传病变是体细胞AKT 1（E17 K）突变，已在4-8%的乳腺癌患者中发现。为了确定这种突变如何导致乳腺肿瘤发生，我们构建了一种基因工程小鼠模型，该模型在乳腺上皮中有条件地表达人AKT 1（E17 K）。尽管AKT 1（E17 K）仅具有弱的组成型活性并且在体外不促进增殖，但它能够逃避负反馈抑制以在体外表现出持续的信号传导动力学。一致地，未交配和经产AKT 1（E17 K）小鼠均发生乳腺增生，但不进展为癌。这种增生伴随着雌激素受体表达的增加，尽管小鼠暴露于雌激素不会促进肿瘤的发展。此外，AKT 1（E17 K）部分通过RTK信号传导的负反馈抑制来防止HER 2驱动的乳腺肿瘤形成。TCGA乳腺癌数据分析显示，在携带AKT 1（E17 K）的人类肿瘤中，各种RTK的mRNA表达、总蛋白水平和磷酸化水平降低。
One of the most frequently deregulated signaling pathways in breast cancer is the PI 3-K/Akt cascade. Genetic lesions are commonly found in PIK3CA, PTEN, and AKT, which lead to excessive and constitutive activation of Akt and downstream signaling that results in uncontrolled proliferation and increased cellular survival. One such genetic lesion is the somatic AKT1(E17K) mutation, which has been identified in 4-8% of breast cancer patients. To determine how this mutation contributes to mammary tumorigenesis, we constructed a genetically engineered mouse model that conditionally expresses human AKT1(E17K) in the mammary epithelium. Although AKT1(E17K) is only weakly constitutively active and does not promote proliferation in vitro, it is capable of escaping negative feedback inhibition to exhibit sustained signaling dynamics in vitro. Consistently, both virgin and multiparous AKT1(E17K) mice develop mammary gland hyperplasia that do not progress to carcinoma. This hyperplasia is accompanied by increased estrogen receptor expression, although exposure of the mice to estrogen does not promote tumor development. Moreover, AKT1(E17K) prevents HER2-driven mammary tumor formation, in part through negative feedback inhibition of RTK signaling. Analysis of TCGA breast cancer data revealed that the mRNA expression, total protein levels, and phosphorylation of various RTKs are decreased in human tumors harboring AKT1(E17K).