To demonstrate a causal role for TGF-β/Smad3 in regulating breast cancer differentiation, we showed that knockdown of Smad3, but not Smad2, was associated with reduced development of well-differentiated glandular-like structures in M3 tumors (Figure 7D,E), and a significant reduction in expression of the differentiated luminal markers cytokeratin 8 (CK8) and ER (Figure 7D,F). This evidence concerns the gene ESR1 and breast carcinoma.