Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America.
PLoS One. 2011;6(9):e24432. doi: 10.1371/journal.pone.0024432. Epub 2011 Sep 7.
Akt1, a serine-threonine protein kinase member of the PKB/Akt gene family, plays critical roles in the regulation of multiple cellular processes, and has previously been implicated in lactation and breast cancer development. In this study, we utilized Akt1+/+ and Akt1-/- C57/Bl6 female mice to assess the role that Akt1 plays in normal mammary gland postnatal development and function. We examined postnatal morphology at multiple time points, and analyzed gene and protein expression changes that persist into adulthood. Akt1 deficiency resulted in several mammary gland developmental defects, including ductal outgrowth and defective terminal end bud formation. Adult Akt1-/- mammary gland composition remained altered, exhibiting fewer alveolar buds coupled with increased epithelial cell apoptosis. Microarray analysis revealed that Akt1 deficiency altered expression of genes involved in numerous biological processes in the mammary gland, including organismal development, cell death, and tissue morphology. Of particular importance, a significant decrease in expression of Btn1a1, a gene involved in milk lipid secretion, was observed in Akt1-/- mammary glands. Additionally, pseudopregnant Akt1-/- females failed to induce Btn1a1 expression in response to hormonal stimulation compared to their wild-type counterparts. Retroviral-mediated shRNA knockdown of Akt1 and Btn1a1 in MCF-7 human breast epithelial further illustrated the importance of Akt1 in mammary epithelial cell proliferation, as well as in the regulation of Btn1a1 and subsequent expression of ß-casein, a gene that encodes for milk protein. Overall these findings provide mechanistic insight into the role of Akt1 in mammary morphogenesis and function.
Akt1 是 PKB/Akt 基因家族的丝氨酸/苏氨酸蛋白激酶成员，在调节多种细胞过程中发挥着关键作用，先前与泌乳和乳腺癌的发展有关。在这项研究中，我们利用 Akt1+/+ 和 Akt1-/- C57/Bl6 雌性小鼠来评估 Akt1 在正常乳腺产后发育和功能中的作用。我们在多个时间点检查了产后形态，并分析了持续到成年的基因和蛋白表达变化。Akt1 缺失导致几种乳腺发育缺陷，包括导管生长和末端芽形成缺陷。成年 Akt1-/- 乳腺组成仍然改变，表现为肺泡芽较少，上皮细胞凋亡增加。微阵列分析显示，Akt1 缺失改变了乳腺中许多生物学过程的基因表达，包括机体发育、细胞死亡和组织形态。特别重要的是，观察到 Akt1-/- 乳腺中与乳脂分泌有关的基因 Btn1a1 的表达显著降低。此外，与野生型相比，假孕 Akt1-/- 雌性在激素刺激下未能诱导 Btn1a1 的表达。MCF-7 人乳腺上皮细胞中 Akt1 和 Btn1a1 的逆转录病毒介导的 shRNA 敲低进一步说明了 Akt1 在乳腺上皮细胞增殖中的重要性，以及对 Btn1a1 的调节和随后对编码乳蛋白的基因β-酪蛋白的表达的重要性。总之，这些发现为 Akt1 在乳腺形态发生和功能中的作用提供了机制上的见解。
