While SMAD4 is generally considered a tumor-suppressor protein, it has also been demonstrated to be involved in metastasis of breast cancer.45 Specifically, SMAD4 knockdown in MDA-MB-231 cells significantly inhibited bone metastasis when injected into nude mice.45 In agreement with this study, our findings suggest that SMAD4 involvement in tumor progression may depend on a variety of factors including tumor microenvironment. Here, SMAD4 is linked to neoplasm.