SMAD4 and breast neoplasm: As for the consequences of SMAD2/3 activation in cancer cells, a study has reported intense immunohistochemical staining of phosphorylated SMAD2 in metastatic breast tumors in the bone and that knockdown of SMAD4, the downstream effector of activated SMAD2/3, was able to decrease bone metastasis of breast cancer in mice [37].