| Autor: |
Magnifico A; Molecular Targeting Unit, Department of Experimental Oncology, National Cancer Institute, Foundation IRCCS, Milan, Italy., Albano L, Campaner S, Campiglio M, Pilotti S, Ménard S, Tagliabue E |
| Jazyk: |
angličtina |
| Zdroj: |
Cancer research [Cancer Res] 2007 Jun 01; Vol. 67 (11), pp. 5308-17. |
| DOI: |
10.1158/0008-5472.CAN-06-3936 |
| Abstrakt: |
In some HER2-positive breast tumors, cell surface overexpression of HER2 is not associated with gene amplification but may instead rest in altered gene transcription, half-life, or recycling of the oncoprotein. Here, we show that HER2 overexpression in HER2 2+ carcinomas is associated with neither an increase in gene transcription nor a deregulation in the ubiquitin-dependent pathways, but instead seems to be regulated by protein kinase Calpha (PKCalpha) activity. The stimulation of PKCalpha up-regulated HER2 expression, whereas PKCalpha inhibition by pharmacologic treatments and PKCalpha-specific small interfering RNA led to a dramatic down-regulation of HER2 levels only in breast cancer cells HER2 2+. Consistent with the in vitro data, our biochemical analysis of HER2 2+ human primary breast specimens revealed significantly higher levels of phosphorylated PKCalpha compared with HER2-negative tumors. Inhibition of HER2 activation by the tyrosine kinase inhibitor lapatinib led to decreased levels of PKCalpha phosphorylation, clearly indicating a cross-talk between PKCalpha and HER2 molecules. These data suggest that HER2 overexpression in HER2 2+ carcinomas is due to an accumulation of the recycled oncoprotein to the cell surface induced by activated PKCalpha. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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