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TGFα expression impairs Trastuzumab-induced HER2 downregulation

Abstract

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.

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Acknowledgements

We thank S Gutkind for kindly providing TGFα cDNA; L Naldini for providing the p156RRLsinPPThCMVMCSpre lentiviral vector; L Granziero for help in flow cytometry studies; L Tamagnone and our colleagues for helpful discussions; A Cignetto for secretarial assistance; and E Wright for editing the manuscript. The technical assistance of L Palmas, R Albano and F Grasso is acknowledged. This work was supported by MURST COFIN to SG, AIRC Grants to SG, PMC and CT, and FIRC Grant to CT.

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Correspondence to Silvia Giordano.

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Valabrega, G., Montemurro, F., Sarotto, I. et al. TGFα expression impairs Trastuzumab-induced HER2 downregulation. Oncogene 24, 3002–3010 (2005). https://doi.org/10.1038/sj.onc.1208478

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