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

Background: 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.Objective: 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). Methods: TNBC MDA-MB-231 cells were treated with either 5 mu M Mont or 25 mu M Sirt or both for 48 h. Alternatively, SEC cells were inoculated in mice to induce breast cancer. After 12 days, the mice were divided into four groups: Untreated SEC group (vehicle), Sirt group (1 mg/kg), Mont group (10 mg/kg), and cotreatment Sirt/ Mont group. The mice groups received the assigned treatment for the consequent 16 days. Results: 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).Conclusion: 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 AKTactivated pathways, with the subsequent inhibition of EMT.

Automated summary

This study aimed to investigate the potential role of Mont, a cysteinyl leukotriene receptor antagonist, in mitigating EMT in TNBC and SEC bearing mice, and the underlying molecular mechanisms with or without sirtuin-1 inhibitor (Sirt). The results showed that Mont and/or Sirt decreased cell proliferation, migration, and suppressed EMT in both in vitro and in vivo experiments. The treatments downregulated sirtuin-1 and vimentin expression, upregulated E-cadherin expression, and inhibited angiogenesis. The cotreatment with Sirt and Mont exhibited more effective anti-tumor activity, possibly due to the inhibition of sirtuin-1 and AKT-activated pathways and subsequent inhibition of EMT.