TY - JOUR
T1 - TGFα expression impairs Trastuzumab-induced HER2 downregulation
AU - Valabrega, Giorgio
AU - Montemurro, Filippo
AU - Sarotto, Ivana
AU - Petrelli, Annalisa
AU - Rubini, Patrizia
AU - Tacchetti, Carlo
AU - Aglietta, Massimo
AU - Comoglio, Paolo Maria
AU - Giordano, Silvia
PY - 2005/4/21
Y1 - 2005/4/21
N2 - The HER2 gene encodes a tyrosine kinase receptor overexpressed in 25-30% of human breast cancers. Clinical trials have shown the efficacy of the anti-HER2 monoclonal antibody Trastuzumab in metastatic breast cancer patients. Nevertheless, 70% of patients are unresponsive from start of treatment and nearly all become unresponsive during treatment. Possible mechanisms for these failures could depend on impairment of the machinery responsible for receptor downregulation. To test this hypothesis, we analysed the genomic sequences encoding regions known to be critical for HER2 downregulation, of both HER2 and of the ubiquitin ligase Cbl. We investigated 63 breast cancers, and found no mutations in these regions. We thus considered alternative mechanisms - such as TGFα production - possibly interfering with HER2 downregulation. In selected cases, by comparing breast cancer neoplastic tissue before and after Trastuzumab treatment, we found induction of TGFα expression. Moreover, by in vitro expression of exogenous TGFα in breast cancer cells, we observed a dramatic reduction in Trastuzumab-induced HER2 endocytosis, downregulation and cell growth inhibition. Our results suggest that unresponsiveness to Trastuzumab may not be due to intrinsic defects in the machinery responsible for HER2 downregulation, but can be associated with a TGFα-related mechanism of escape to HER2 downregulation.
AB - The HER2 gene encodes a tyrosine kinase receptor overexpressed in 25-30% of human breast cancers. Clinical trials have shown the efficacy of the anti-HER2 monoclonal antibody Trastuzumab in metastatic breast cancer patients. Nevertheless, 70% of patients are unresponsive from start of treatment and nearly all become unresponsive during treatment. Possible mechanisms for these failures could depend on impairment of the machinery responsible for receptor downregulation. To test this hypothesis, we analysed the genomic sequences encoding regions known to be critical for HER2 downregulation, of both HER2 and of the ubiquitin ligase Cbl. We investigated 63 breast cancers, and found no mutations in these regions. We thus considered alternative mechanisms - such as TGFα production - possibly interfering with HER2 downregulation. In selected cases, by comparing breast cancer neoplastic tissue before and after Trastuzumab treatment, we found induction of TGFα expression. Moreover, by in vitro expression of exogenous TGFα in breast cancer cells, we observed a dramatic reduction in Trastuzumab-induced HER2 endocytosis, downregulation and cell growth inhibition. Our results suggest that unresponsiveness to Trastuzumab may not be due to intrinsic defects in the machinery responsible for HER2 downregulation, but can be associated with a TGFα-related mechanism of escape to HER2 downregulation.
KW - Cbl ubiquitin ligase
KW - HER2
KW - Receptor degradation
KW - TGFα
UR - http://www.scopus.com/inward/record.url?scp=18344382431&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=18344382431&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1208478
DO - 10.1038/sj.onc.1208478
M3 - Article
C2 - 15735715
AN - SCOPUS:18344382431
VL - 24
SP - 3002
EP - 3010
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 18
ER -