Endoplasmic reticulum stress inhibits 3D Matrigel-induced vasculogenic mimicry of breast cancer cells via TGF-β1/Smad2/3 and β-catenin signaling.

Endoplasmic reticulum (ER) stress is a cellular stress condition involving disturbance in the folding capacity of the ER caused by endogenous and exogenous factors. ER stress signaling pathways affect tumor malignant growth, angiogenesis and progression, and promote the antitumor effects of certain drugs. However, the impact of ER stress on the vasculogenic mimicry (VM) phenotype of cancer cells has not been well addressed. VM is a phenotype that mimics vasculogenesis by forming patterned tubular networks, which are related to stemness and aggressive behaviors of cancer cells. In this study, we used tunicamycin (TM), the unfolded protein response (UPR)-activating agent, to induce ER stress in aggressive triple-negative MDA-MB-231 breast cancer cells, which exhibit a VM phenotype in 3D Matrigel cultures. TM-induced ER stress was able to inhibit the VM phenotype. In addition to the tumor spheroid phenotype observed upon inhibiting the VM phenotype, we observed alterations in glycosylation of integrin β1, loss of VE-cadherin and a decrease in stem cell marker Bmi-1. Further study revealed decreased activated transforming growth factor β1, Smad2/3, Phospho-Smad2 and β-catenin. β-Catenin knockdown markedly inhibited the VM phenotype and resulted in the loss of VE-cadherin. The data suggest that the activation of ER stress inhibited VM phenotype formation of breast cancer cells via both the transforming growth factor β1/Smad2/3 and β-catenin signaling pathways. The discovery of prospective regulatory mechanisms involved in ER stress and VM in breast cancer could lead to more precisely targeted therapies that inhibit vessel formation and affect tumor progression.