HER2/EGFR-AKT signaling switches TGF-{beta} from inhibiting cell proliferation to promoting cell migration in breast cancer

Transforming growth factor-β (TGF-β) signaling inhibits cell proliferation to block cancer initiation, yet it also enhances metastasis to promote malignancy during breast cancer development. The mechanisms underlying these differential effects are still unclear. Here we report that HER2/EGFR signaling switches TGF-β function in breast cancer cells from anti-proliferation to cancer promotion. Inhibition of HER2/EGFR activity attenuated TGF-β-induced epithelial-mesenchymal transition and migration but enhanced the anti-proliferative activity of TGF-β. Activation of HER2/EGFR induced phosphorylation of Smad3 at Ser208 of the linker region through AKT, which promoted the nuclear accumulation of Smad3 and subsequent expression of the genes related to EMT and cell migration. In contrast, HER2/EGFR signaling had no effects on the nuclear localization of Smad2. Knockdown of Smad3, but not Smad2, blocked TGF-β-induced breast cancer cell migration. We observed a positive correlation between the nuclear localization of Smad3 and HER2 activation in advanced human breast cancers. Our results demonstrate a key role of HER2/EGFR in differential regulation of Smad3 activity to shift TGF-β function from anti- to pro-tumorigenic during breast cancer development.

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