| resistance.
Hypoxia, the epithelial-mesenchymal transition (EMT), and cancer stem cells (CSCs) are known as essential
factors for VM formation. Also, melatonin is an amino acid-derived hormone with many anti-tumor effects.
Despite the antitumor effects of melatonin, its effect on VM formation in breast cancer has not been considered
yet, so we investigated the effect of melatonin on VM formation through EMT process under hypoxia conditions
in breast CSCs. The CSCs percentage and VM formation were determined in MCF-7 and MDA-MB-231, respectively.
Also, analysis of HIF-1α expression under hypoxia in MDA-MB-231 and MCF-7 cell lines was performed
using Western blot. The effect of melatonin on the VM formation, invasion, and migration was also investigated.
Moreover, the effect of melatonin on the expression EMT markers was evaluated. CD44+ CD24-phenotype as
CSCs marker in MDA-MB-231 cell line, was 80.8%, while it was 11.1% in MCF-7 cell line. HIF-1α expression was
up-regulated in the VM-positive breast cancer cell line MDA-MB-231, and consequently, affected the expression
of the EMT markers E-cadherin, vimentin, snail, and MMP9. Melatonin had significant effect on EMT and formations
of VM in breast CSCs. Melatonin could prevent the formation of VM by affecting the important molecules
involved in the formation of VM structures and the EMT. Moreover, our data clearly showed that, melatonin represents
molecule with significant anti-cancer activities that may potentially optimize the management of breast
cancer through the overcoming drug resistance in anti-angiogenic drugs. |