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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]

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