Suppression of epithelial-mesenchymal transition and SIRT1/AKT signaling pathway in breast cancer by montelukast

Abstract

Breast cancer is usually associated with metastatic features, poor prognosis, and high mortality. The epithelial-mesenchymal transition (EMT) process has been implicated in the initiation and metastasis of breast cancer. The study aimed to investigate the possible role of montelukast (Mont), the cysteinyl leukotriene receptor (CystLT1R) antagonist, in mitigating EMT in triple-negative breast cancer (TNBC) (in vitro study) and solid Ehrlich carcinoma (SEC) bearing mice (in vivo study) as well as to clarify the underlying molecular mechanisms in the presence and absence of sirtuin-1 inhibitor (sirtinol; Sirt). TNBC MDA-MB-231 cells were treated with either 5μM Mont or 25μM Sirt or both for 48h. Alternatively, SEC cells were inoculated in mice to induce breast cancer. After 12days, the mice were divided into four groups: Untreated SEC group (vehicle), Sirt group (1mg/kg), Mont group (10mg/kg), and cotreatment Sirt/Mont group. The mice groups received the assigned treatment for the consequent 16days. Mont and/or Sirt decreased cell proliferation, migration and suppressed EMT in both in vitro and in vivo experiments. All treatments downregulated sirtuin-1 and vimentin expression but upregulated E-cadherin expression. Furthermore, all treatments retarded angiogenesis as evidenced by decreased VEGF expression. These findings were associated with suppressing active protein kinase B (p-AKT). Cotreatment with Sirt and Mont proved more effective anti-tumor activity in TNBC cell line and in SEC bearing mice than either treatment alone, which could be attributed to the inhibition of sirtuin-1 and AKT- activated pathways, with the subsequent inhibition of EMT.