Studies indicate that interaction between HER2 and TGF-β takes place in several levels including; (i) suppression of Smad-dependent transcriptional regulation and its downstream target genes by HER2; (ii) activation of the HER2 downstream pathways (PI3K/AKT and MAPK pathways) by TGF-β in a Smad-independent manner and (iii) modification of the tumor microenvironment by secretory mediators that are regulated by both downstream mediators of HER2 and TGF-β receptors [183] (Figure 1). This evidence concerns the gene AKT1 and neoplasm.