1. ¹Division of Medical Oncology, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Str. Prov. 142, Km 3.95, 10060 Candiolo, Italy
2. ²Department of Pathology, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Str. Prov. 142, Km 3.95, 10060 Candiolo, Italy
3. ³Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Str. Prov. 142, Km 3.95, 10060 Candiolo, Italy
4. ⁴Department of Experimental Medicine, FIRC Institute of Molecular Oncology (IFOM), Anatomy Section, University of Genoa, Via deToni 14, 16132 Genoa, Italy

Correspondence: S Giordano, E-mail: silvia.giordano@ircc.it

Received 15 October 2004; Revised 13 December 2004; Accepted 27 December 2004; Published online 14 February 2005.

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 TGF production – possibly interfering with HER2 downregulation. In selected cases, by comparing breast cancer neoplastic tissue before and after Trastuzumab treatment, we found induction of TGF expression. Moreover, by in vitro expression of exogenous TGF 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 TGF-related mechanism of escape to HER2 downregulation.