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 language | English |
|---|---|
| Pages (from-to) | 5308-5317 |
| Number of pages | 10 |
| Journal | Cancer Research |
| Volume | 67 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - Jun 1 2007 |
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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 journal › Article
}
TY - JOUR
T1 - Protein kinase CA determines HER2 fate in breast carcinoma cells with HER2 protein overexpression without gene amplification
AU - Magnifico, Alessandra
AU - Albano, Luisa
AU - Campaner, Stefano
AU - Campiglio, Manuela
AU - Pilotti, Silvana
AU - Ménard, Sylvie
AU - Tagliabue, Elda
PY - 2007/6/1
Y1 - 2007/6/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-06-3936
DO - 10.1158/0008-5472.CAN-06-3936
M3 - Article
VL - 67
SP - 5308
EP - 5317
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 11
ER -