The migration of metastatic breast cancer cells is regulated by matrix stiffness via YAP signalling.

Matrix stiffness is a driver of breast cancer progression and mechanosensitive transcriptional activator YAP plays an important role in this process. However, the interplay between breast cancer and matrix stiffness, and the significance of this interplay remained largely unknown. Here, we showed an increase in YAP nuclear localization and a higher proliferation rate in both highly metastatic MDA-MB-231 cells and the non-metastatic counterpart MCF-7 cells when they were exposed to the stiff matrix. However, in response to the stiff matrix highly metastatic MDA-MB-231 cells instead of MCF-7 cells exhibited upregulated mobility, which was shown to be YAP-dependent. Consistently, MDA-MB-231 cells exhibited different focal adhesion dynamics from MCF-7 cells in response to matrix stiffness. These results suggested a YAP-dependent mechanism through which matrix stiffness regulates the migratory potential of metastatic breast cancer cells.

Autophagy promotes triple negative breast cancer metastasis via YAP nuclear localization.

The triple-negative breast cancer (TNBC) subtype is the most aggressive form of invasive breast cancer. Although autophagy is critical to the progression of TNBC, the mechanism of autophagy in regulating the metastatic potential of TNBC still remains unclear. Recently, the effector of the Hippo signaling pathway yes-associated protein (YAP) was shown to promote autophagy. To investigate autophagy regulation in YAP signaling in the context of cancer metastasis, we performed profiling analysis of YAP signaling, YAP subcellular localization, autophagosome formation and cell invasiveness in TNBC cell lines (MDA-MB-231 and Hs 578T) versus estrogen receptor (ER) positive breast cancer cell line MCF7. Our results showed that YAP transcriptional and protein expression was significantly upregulated in TNBC. When we triggered autophagy response in TNBC, YAP translocated into the nucleus and the expression of YAP target gene ankyrin repeat domain 1 (ANKRD1) increased remarkably. The correlation between autophagy response and YAP expression in TNBC was confirmed at the single-cell level. Furthermore, the inhibition of YAP nuclear entry greatly impeded the migration and invasion of TNBC cells while it did not affect the mobility of ER positive breast cancer cells. Therefore, this research established the autophagy-YAP-metastasis axis in TNBC and sheds light on the application of targeting YAP for TNBC therapeutics.