MECHANISMS OF SIGNAL TRANSDUCTION
HER-2/neu Blocks Tumor Necrosis Factor-induced Apoptosis via the Akt/NF-κB Pathway*

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Overexpression of HER-2/neucorrelates 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 ofHER-2/neu-induced TNF resistance is unknown. Here we report that HER-2/neu activates Akt and NF-κB without extracellular stimulation. Blocking of the Akt pathway by a dominant-negative Akt sensitizes theHER-2/neu-overexpressing cells to TNF-induced apoptosis and inhibites IκB kinases, IκB phosphorylation, and NF-κB activation. Our results suggested that HER-2/neu constitutively activates the Akt/NF-κB anti-apoptotic cascade to confer resistance to TNF on cancer cells and reduce host defenses against neoplasia.

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This work was supported by Grants R01-CA58880 and R01-CA77858 (to M.-C. H.) and Cancer Core Grant 16672 from the NCI, National Institutes of Health, by the Nellie Connally Breast Cancer Research Fund, and by a Faculty Achievement Award at M. D. Anderson Cancer Center (to M.-C. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These two authors are recipients, respectively, of postdoctoral and predoctoral fellowships from the United States Department of Defense (DOD) Breast Cancer Research Training Grant (DAMD17-99-1-9264).

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Predoctoral fellow of the DOD Breast Cancer Research Program (DAMD17-98-1-8242).