Her2 activates NF-kappaB and induces invasion through the canonical pathway involving IKKalpha.
The membrane bound receptor tyrosine kinase Her2 is overexpressed in approximately 30% of human breast cancers, which correlates with poor prognosis. Her2-induced signaling pathways include MAPK and PI3K/Akt, of which the latter has been shown to be critical for Her2(+) breast cancer cell growth and survival. In addition, the NF-kappaB pathway has been shown to be activated downstream of Her2 overexpression; however, the mechanisms leading to this activation are not currently clear. Using Her2(+)/ER(-) breast cancer cells, we show that Her2 activates NF-kappaB through the canonical pathway which, surprisingly, involves IKKalpha. Knockdown of IKKalpha led to a significant decrease in transcription levels of multiple NF-kappaB-regulated cytokine and chemokine genes. siRNA-mediated knockdown of IKKalpha resulted in a decrease in cancer cell invasion, but had no effect on cell proliferation. Inhibition of the PI3K/Akt pathway had no effect on NF-kappaB activation, but significantly inhibited cell proliferation. Our study suggests different roles for the NF-kappaB and PI3K pathways downstream of Her2, leading to changes in invasion and proliferation of breast cancer cells. In addition this work indicates the importance of IKKalpha as a mediator of Her2-induced tumor progression.
Merkhofer
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EC
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Cogswell
P
P
Baldwin
A S
AS
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000503:physiopathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000494:pharmacology*
D051550:I-kappa B Kinase; D016328:NF-kappa B; D018719:Erb-b2 Receptor Tyrosine Kinases; D025521:Tumor Suppressor Proteins; C508053:ERBB2 protein, human