Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490 Buenos Aires (1428), Argentina.
Centro de Investigaciones Inmunológicas Básicas y Aplicadas. Fac. Ciencias Médicas - Universidad Nacional La Plata (1900), Argentina.
Sci Rep. 2017 Mar 13;7:44244. doi: 10.1038/srep44244.
The purpose of this study was to elucidate the mechanisms associated with the specific effects of AKT1 and AKT2 isoforms in breast cancer progression. We modulated the abundance of specific AKT isoforms in IBH-6 and T47D human breast cancer cell lines and showed that AKT1 promoted cell proliferation, through S6 and cyclin D1 upregulation, but it inhibited cell migration and invasion through β1-integrin and focal adhesion kinase (FAK) downregulation. In contrast, AKT2 promoted cell migration and invasion through F-actin and vimentin induction. Thus, while overexpression of AKT1 promoted local tumor growth, downregulation of AKT1 or overexpression of AKT2 promoted peritumoral invasion and lung metastasis. Furthermore, we evaluated The Cancer Genome Atlas (TCGA) dataset for invasive breast carcinomas and found that increased AKT2 but not AKT1 mRNA levels correlated with a worse clinical outcome. We conclude that AKT isoforms play specific roles in different steps of breast cancer progression, with AKT1 involved in the local tumor growth and AKT2 involved in the distant tumor dissemination, having AKT2 a poorer prognostic value and consequently being a worthwhile target for therapy.
本研究旨在阐明 AKT1 和 AKT2 同工型在乳腺癌进展中特定作用相关的机制。我们在 IBH-6 和 T47D 人乳腺癌细胞系中调节特定 AKT 同工型的丰度，结果表明 AKT1 通过上调 S6 和细胞周期蛋白 D1 促进细胞增殖，但通过下调 β1-整联蛋白和粘着斑激酶（FAK）抑制细胞迁移和侵袭。相反，AKT2 通过诱导 F-肌动蛋白和波形蛋白促进细胞迁移和侵袭。因此，虽然 AKT1 的过表达促进局部肿瘤生长，但 AKT1 的下调或 AKT2 的过表达促进肿瘤周围侵袭和肺转移。此外，我们还评估了浸润性乳腺癌的癌症基因组图谱（TCGA）数据集，发现 AKT2 而不是 AKT1 mRNA 水平的增加与更差的临床结局相关。我们的结论是，AKT 同工型在乳腺癌进展的不同阶段发挥特定作用，AKT1 参与局部肿瘤生长，AKT2 参与远处肿瘤播散，AKT2 具有更差的预后价值，因此是治疗的有价值靶点。
