HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-κB pathway

Overexpression of HER-2/neu correlates with poor survival of breast and ovarian cancer patients and induces resistance to tumor necrosis factor (TNF), which causes cancer cells to escape from host immune defenses. The mechanism of HER-2/neu-induced TNF resistance is unknown. Here we report that HER-2/neu activates Akt and NF-KB without extracellular stimulation. Blocking of the Akt pathway by a dominant-negative Akt sensitizes the HER-2/neu-overexpressing cells to TNF-induced apoptosis and inhibites I kappa B kinases, I kappa B phosphorylation, and NF-KB activation. Our results suggested that HER-2/neu constitutively activates the Akt/NF-kappa B anti-apoptotic cascade to confer resistance to TNF on cancer cells and reduce host defenses against neoplasia.