Maroulakou Ioanna G, Oemler William, Naber Stephen P, Klebba Ina, Kuperwasser Charlotte, Tsichlis Philip N
Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA.
J Cell Physiol. 2008 Nov;217(2):468-77. doi: 10.1002/jcp.21518.
The three Akt isoforms differ in their ability to transduce oncogenic signals initiated by the Neu and PyMT oncogenes in mammary epithelia. As a result, ablation of Akt1 inhibits and ablation of Akt2 accelerates mammary tumor development by both oncogenes, while ablation of Akt3 is phenotypically almost neutral. Since the risk of breast cancer development in humans correlates with multiple late pregnancies, we embarked on a study to determine whether individual Akt isoforms also differ in their ability to transduce hormonal and growth factor signals during pregnancy, lactation and post-lactation involution. The results showed that the ablation of Akt1 delays the differentiation of the mammary epithelia during pregnancy and lactation, and that the ablation of Akt2 has the opposite effect. Finally, ablation of Akt3 results in minor defects, but its phenotype is closer to that of the wild type mice. Whereas the phenotype of the Akt1 ablation is cell autonomous, that of Akt2 is not. The ablation of Akt1 promotes apoptosis and accelerates involution, whereas the ablation of Akt2 inhibits apoptosis and delays involution. Mammary gland differentiation during pregnancy depends on the phosphorylation of Stat5a, which is induced by prolactin, a hormone that generates signals transduced via Akt. Here we show that the ablation of Akt1, but not the ablation of Akt2 or Akt3 interferes with the phosphorylation of Stat5a during late pregnancy and lactation. We conclude that the three Akt isoforms have different roles in mammary gland differentiation during pregnancy and this may reflect differences in hormonal signaling.
三种Akt亚型在转导由Neu和PyMT致癌基因在乳腺上皮细胞中引发的致癌信号的能力上存在差异。因此，敲除Akt1会抑制，而敲除Akt2会加速这两种致癌基因引发的乳腺肿瘤发展，而敲除Akt3在表型上几乎是中性的。由于人类患乳腺癌的风险与多次晚育相关，我们开展了一项研究，以确定在妊娠、哺乳和哺乳后退化过程中，各个Akt亚型在转导激素和生长因子信号的能力上是否也存在差异。结果表明，敲除Akt1会延迟妊娠和哺乳期乳腺上皮细胞的分化，而敲除Akt2则有相反的效果。最后，敲除Akt3会导致轻微缺陷，但其表型更接近野生型小鼠。Akt1敲除的表型是细胞自主性的，而Akt2敲除的表型则不是。敲除Akt1会促进细胞凋亡并加速退化，而敲除Akt2会抑制细胞凋亡并延迟退化。妊娠期间乳腺的分化取决于Stat5a的磷酸化，Stat5a的磷酸化由催乳素诱导，催乳素是一种通过Akt转导信号的激素。在这里我们表明，敲除Akt1，而不是敲除Akt2或Akt3，会在妊娠晚期和哺乳期干扰Stat5a的磷酸化。我们得出结论，三种Akt亚型在妊娠期间乳腺分化中具有不同作用，这可能反映了激素信号传导的差异。
