Journal
ONCOGENE
Volume 21, Issue 22, Pages 3532-3540Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1205438
Keywords
AKT; HER-2/neu; overexpression; breast tumors; apoptosis; hypoxia
Funding
- NCI NIH HHS [P30 CA006927, R01 CA077429, CA06927, CA77429] Funding Source: Medline
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Amplification or overexpression of the HER-2/neu gene in breast cancers is associated with aggressive behavior and resistance to therapeutic regimens. The molecular mechanisms that contribute to therapeutic resistance/survival of HER-2/neu-overexpressing tumor cells have not been well defined. To determine if phosphatidylinositol 3-kinase/AKT signaling contributes to cell survival in HER-2/neu-positive breast cancers, we performed immunohistochemical analyses to evaluate expression of HER-2/neu and AKT in a series of 52 breast carcinomas. Elevated expression of HER-2/neu was found to correlate with overexpression of AKT2 protein and activation of AKT kinase. HER-2/neu-overexpressing breast cancer cell lines were resistant to apoptosis induced by UV treatment and hypoxia, which was suppressed in the presence of the phosphatidylinositol 3-kinase inhibitors LY294002 and wortmannin, indicating a link between AKT activation and stress resistance in HER-2/neu-overexpressing cells. These observations suggest that AKT signaling augments resistance to stress-induced apoptosis in breast cancer cells over-expressing HER-2/neu.
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