AKT1 and AKT2 isoforms play distinct roles during breast cancer progression through the regulation of specific downstream proteins

• Published in: Scientific reports 2017-03, Vol.7 (1), p.44244, Article 44244
• Main Authors: Riggio, Marina, Perrone, María C., Polo, María L., Rodriguez, María J., May, María, Abba, Martín, Lanari, Claudia, Novaro, Virginia
• Format: Article
• Language: English
• Subjects: 13/106; 13/51; 14; 14/19; 631/337; 64; 64/60; 692/4028; Actin; Actins - genetics; Actins - metabolism; AKT protein; AKT1 protein; AKT2 protein; Animals; Breast cancer; Breast carcinoma; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell proliferation; Cell Proliferation - genetics; Cyclin D1; Cyclin D1 - genetics; Cyclin D1 - metabolism; Disease Progression; Female; Focal adhesion kinase; Gene Expression Regulation, Neoplastic; Genomes; Humanities and Social Sciences; Humans; Invasiveness; Isoforms; Kinases; Metastases; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; mRNA; multidisciplinary; Neoplasm Invasiveness; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Science; Survival Analysis; Transplantation, Heterologous; Tumor cell lines; Vimentin
• ISSN: 2045-2322; 2045-2322
• 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.