Previous results indicated that Heregulin (HRG) increased cell migration through ErbB3/P-Rex/Rac1 signaling activation in luminal breast cancer (BC) cells, and that this pathway also induced TGFβ2 expression, a molecule associated with migratory processes. Therefore, our goal was to establish the role of the TGFβ canonical pathway on Hrg-induced BC cell migration. To that end, we carried out experiments using specific pharmacological inhibitors and transient gene silencing to block mediators of the involved pathways. Analysis of mRNA and protein levels, as well as wound-healing assays in luminal BC cells were performed. Our results show that HRG induced not only TGFβ2, but also TGFβ1, TGFBR1, TGFBR2, SMAD3, and SMAD4 expression, and preliminary results indicate that Rac1 could be involved in these pathways. Supporting these data, we found positive correlations between HRG and TGFβ1, TGFβ2, TGFβ3, and TGFBR3 protein content in proteomic data sets from BC samples. In addition, HRG treatment induced phosphorylation and nuclear translocation of SMAD3, but this activation was blocked by adding either ErbB2 or TGFBR1 inhibitors. Furthermore, blocking TGFBR1 also inhibited HRG-induced cell migration. Importantly, after HRG treatment, SMAD3 phosphorylation was not affected by P-REX1 silencing and Rac1 activation increased when TGFBR1 was inhibited. This suggests that the HRG-induced TGFβ pathway does not contribute, but competes with activation of P-REX1/Rac1 signaling. Our results indicate that induction of TGFB ligands and SMAD-dependent pathway activation is required for HRG-induced migration in BC luminal cells. We are currently analyzing the impact of clinically relevant pharmacological ErbBs inhibitors to investigate the most effective way to reduce the combined effects triggered by HRG on BC cell migration and invasiveness. We believe our findings may contribute to the search for new combination therapies, which may lead to more successful treatments for luminal BC.