Our novel observation that the direction of regulation of Smad3 target genes by TGF-β can differ in vitro and in vivo identifies an additional new facet of TGF-β contextuality that is highlighted by the effects of TGF-β on ANGPTL4. ANGPTL4 was previously identified as a metastasis-promoting gene that was upregulated by TGF-β in MDA-MB-231 cells, an ER-negative breast cancer model in which TGF-β has lost its tumor-suppressive activity and instead promotes progression [34]. This evidence concerns the gene SMAD3 and neoplasm.