SMAD2 and breast cancer: Specifically, EZH2 works as a transcription co-factor of RNA Pol II to increase ITGB1 gene transcription; the increased integrin β1 induces phosphorylation of Y397 on FAK leading to FAK activation; activated pY397-FAK phosphorylates TGFβRI at Y182 that increases TGFβRI’s binding affinity for TGFβRII in response to TGFβ exposure, thereby triggering pS465/467-Smad2 that induces the downstream effector PTHLH; PTHLH accelerates osteolysis leading to more TGFβ release, and thus driving the feed-forward vicious cycle of breast cancer bone metastasis outgrowth (Fig. 7).