These findings are important for defining the tumorigenic roles of ErbB receptors and HRG as well as Smad2 activation in breast cancers, because HRG-β1 can overcome the inhibitory effects of anti-EGFR therapies on cell growth and activate invasion in tamoxifen-resistant cells through promotion of ErbB3/ErbB2 heterodimerization and activation of the PI3k/Akt signaling pathway [34]. Here, SMAD2 is linked to breast carcinoma.