Matrix stiffness modulates ILK-mediated YAP activation to control the drug resistance of breast cancer cells

One of the hallmarks of cancer progression is strong drug resistance during clinical treatments. The tumor microenvironment is closely associated with multidrug resistance, the optimization of tumor microenvironments may have a strong therapeutic effect. In this study, we configured polyacrylamide hydrogels of varying stiffness [low (10 kPa), intermediate (38 kPa) and high (57 kPa)] to simulate tissue physical matrix stiffness across different stages of breast cancer. After treatment with doxorubicin, cell survival rates on intermediate stiffness substrate are significantly higher. We find that high expression of ILK and YAP reduces the survival rates of breast cancer patients. Drug resistance is closely associated with the inactivation of the hippo pathway protein Merlin/MST/LATS and the activation of YAP. These results not only highlight the understanding of drug resistance mechanisms but also serve as a new basis for developing breast cancer treatment delivery systems. • High expressions of ILK and YAP reduce the survival rates of breast cancer patients. • ILK and YAP inhibitions result in lower levels of cell drug resistance. • Drug resistance is closely associated with the inactivation of the hippo pathway of Merlin/MST/LATS. • Matrix stiffness regulates the drug resistance of breast cancer cells through ILK-mediated YAP activation.