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

Alessandra Magnifico, Luisa Albano, Stefano Campaner, Manuela Campiglio, Silvana Pilotti, Sylvie Ménard, Elda Tagliabue

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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 Cα (PKCα) activity. The stimulation of PKCα up-regulated HER2 expression, whereas PKCα inhibition by pharmacologic treatments and PKCα-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 PKCα compared with HER2-negative tumors. Inhibition of HER2 activation by the tyrosine kinase inhibitor lapatinib led to decreased levels of PKCα phosphorylation, clearly indicating a cross-talk between PKCα 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 PKCα.

Original languageEnglish
Pages (from-to)5308-5317
Number of pages10
JournalCancer Research
Volume67
Issue number11
DOIs
Publication statusPublished - Jun 1 2007

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Gene Amplification
Protein Kinases
Protein Kinase C
Breast Neoplasms
Proteins
Oncogene Proteins
Carcinoma
Recycling
Ubiquitin
Protein-Tyrosine Kinases
Small Interfering RNA
Genes
Half-Life
Breast
Down-Regulation
Phosphorylation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Protein kinase CA determines HER2 fate in breast carcinoma cells with HER2 protein overexpression without gene amplification. / Magnifico, Alessandra; Albano, Luisa; Campaner, Stefano; Campiglio, Manuela; Pilotti, Silvana; Ménard, Sylvie; Tagliabue, Elda.

In: Cancer Research, Vol. 67, No. 11, 01.06.2007, p. 5308-5317.

Research output: Contribution to journalArticle

Magnifico, Alessandra ; Albano, Luisa ; Campaner, Stefano ; Campiglio, Manuela ; Pilotti, Silvana ; Ménard, Sylvie ; Tagliabue, Elda. / Protein kinase CA determines HER2 fate in breast carcinoma cells with HER2 protein overexpression without gene amplification. In: Cancer Research. 2007 ; Vol. 67, No. 11. pp. 5308-5317.
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