EZH2 engages TGF beta signaling to promote breast cancer bone metastasis via integrin beta 1-FAK activation

Bone metastases occur in 50-70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2 (EZH2) is correlated with breast cancer metastasis, but its function in bone metastasis hasn't been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGF beta) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increases ITGB1, which encodes for integrin beta 1. Integrin beta 1 activates focal adhesion kinase (FAK), which phosphorylates TGF beta receptor type I (TGF beta RI) at tyrosine 182 to enhance its binding to TGF beta receptor type II (TGF beta RII), thereby activating TGF beta signaling. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitors effectively inhibit breast cancer bone metastasis in vivo. Overall, we find that the EZH2-integrin beta 1-FAK axis cooperates with the TGF beta signaling pathway to promote bone metastasis of breast cancer. Breast cancer cells are known to metastasize to the bone but why the cells should migrate and metastasize to this particular organ is not clearly understood. Here, the authors show that EZH2 activates an integrin B1 and FAK signaling pathway in breast cancer cells, which activates TGFB signaling to drive metastasis in the bone.