This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Magnifico, A. Articles by Tagliabue, E. Search for Related Content PubMed PubMed Citation Articles by Magnifico, A. Articles by Tagliabue, E.

Protein Kinase C Determines HER2 Fate in Breast Carcinoma Cells with HER2 Protein Overexpression without Gene Amplification

¹ Molecular Targeting Unit, Department of Experimental Oncology and ² Department of Pathology, National Cancer Institute, Foundation IRCCS; ³ Department of Experimental Oncology, European Institute of Oncology, Milan, Italy

Requests for reprints: Sylvie Ménard, Molecular Targeting Unit, Department of Experimental Oncology, National Cancer Institute, Via Venezian 1, Milan 20133, Italy. Phone: 39-02-23902572; Fax: 39-02-23903073; E-mail: sylvie.menard{at}istitutotumori.mi.it.

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 C (PKC) activity. The stimulation of PKC up-regulated HER2 expression, whereas PKC inhibition by pharmacologic treatments and PKC-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 PKC compared with HER2-negative tumors. Inhibition of HER2 activation by the tyrosine kinase inhibitor lapatinib led to decreased levels of PKC phosphorylation, clearly indicating a cross-talk between PKC 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 PKC. [Cancer Res 2007;67(11):5308–17]

This article has been cited by other articles:

				A. J. Redig, A. Sassano, B. Majchrzak-Kita, E. Katsoulidis, H. Liu, J. K. Altman, E. N. Fish, A. Wickrema, and L. C. Platanias Activation of Protein Kinase C{eta} by Type I Interferons J. Biol. Chem., April 17, 2009; 284(16): 10301 - 10314. [Abstract] [Full Text] [PDF]

				A. Magnifico, L. Albano, S. Campaner, D. Delia, F. Castiglioni, P. Gasparini, G. Sozzi, E. Fontanella, S. Menard, and E. Tagliabue Tumor-Initiating Cells of HER2-Positive Carcinoma Cell Lines Express the Highest Oncoprotein Levels and Are Sensitive to Trastuzumab Clin. Cancer Res., March 15, 2009; 15(6): 2010 - 2021. [Abstract] [Full Text] [PDF]

				M. Lerdrup, S. Bruun, M. V. Grandal, K. Roepstorff, M. M. Kristensen, A. M. Hommelgaard, and B. van Deurs Endocytic Down-Regulation of ErbB2 Is Stimulated by Cleavage of Its C-Terminus Mol. Biol. Cell, September 1, 2007; 18(9): 3656 - 3666. [Abstract] [Full Text] [PDF]