Such observation are in accordance with previous studies, in xenograft models and cell lines, showing that SMAD4 signaling is needed for the formation of osteolytic bone metastases, an observation that was confirmed by the knockdown of SMAD4 in breast cancer cells which could protect against bone metastasis in nude mice with significantly increasing metastasis free survival [30, 31]. Here, SMAD4 is linked to breast cancer.