Breast Cancer Research Today is a free monthly online journal that collates and summarizes the latest research about Breast Cancer, including details on symptoms, genetics, screening, treatment, information.

Protein kinase Calpha determines HER2 fate in breast carcinoma cells with HER2 protein overexpression without gene amplification.

Magnifico A, Albano L, Campaner S, Campiglio M, Pilotti S, Ménard S, Tagliabue E

Molecular Targeting Unit, Department of Experimental Oncology, National Cancer Institute, Foundation IRCCS, Milan, Italy.

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.

Published 4 June 2007 in Cancer Res, 67(11): 5308-17.
Full-text of this article is available online (may require subscription).

© 2004-2008 Breast Cancer Research Today. All Rights Reserved.