Abstract
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.
Highlights
The purpose of this study was to elucidate the mechanisms associated with the specific effects of AKT1 and AKT2 isoforms in breast cancer progression
Despite the huge amount of clinical trials targeting the pathway in cancer, the only approved drug is Everolimus, an mTOR inhibitor, in combination with Exemestane for advanced hormone receptor positive (HR+)/HER2-negative (HER2−)breast cancer that progressed on endocrine therapy[14,15]
To assess whether the AKT1 and AKT2 tumor levels are related to breast cancer progression in patients, we evaluated 1105 samples of invasive breast carcinoma available from The Cancer Genome Atlas (TCGA) website[40,41] consisting of data sets with DNA amplifications, mutations, deletions and mRNA up- and downregulations (Fig. 5a)
Summary
The purpose of this study was to elucidate the mechanisms associated with the specific effects of AKT1 and AKT2 isoforms in breast cancer progression. It has been demonstrated that the overactivation of the pathway contributes to tumorigenesis and tumor progression in the mammary gland through growth factor independent cell proliferation[6], cell invasion[7], endocrine receptor deregulation[8,9] and resistance to therapy[10]. PI3KCA mutations have been shown to activate downstream kinase AKT and induce oncogenic transformation[12,13] these lesions render tumors highly sensitive to PI3K/AKT/mTOR-directed therapeutic inhibition. Despite the huge amount of clinical trials targeting the pathway in cancer, the only approved drug is Everolimus, an mTOR inhibitor, in combination with Exemestane for advanced hormone receptor positive (HR+)/HER2-negative (HER2−)breast cancer that progressed on endocrine therapy[14,15]. In an ErbB2-induced model, Hutchinson et al.[24] showed that activation of www.nature.com/scientificreports/
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