title: TGFalpha 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 TGFalpha production -- possibly interfering with HER2 downregulation. In selected cases, by comparing breast cancer neoplastic tissue before and after Trastuzumab treatment, we found induction of TGFalpha expression. Moreover, by in vitro expression of exogenous TGFalpha 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 TGFalpha-related mechanism of escape to HER2 downregulation.
authors.affiliation: Division of Medical Oncology, Institute for Cancer Research and Treatment, University of Turin Medical School, Str. Prov. 142, Km 3.95, 10060 Candiolo, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Valabrega
authors.forename: Filippo
authors.initials: F
authors.lastname: Montemurro
authors.forename: Ivana
authors.initials: I
authors.lastname: Sarotto
authors.forename: Annalisa
authors.initials: A
authors.lastname: Petrelli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Rubini
authors.forename: Carlo
authors.initials: C
authors.lastname: Tacchetti
authors.forename: Massimo
authors.initials: M
authors.lastname: Aglietta
authors.forename: Paolo Maria
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D015536:Down-Regulation; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D017434:Protein Structure, Tertiary; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics*; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016211:Transforming Growth Factor alpha; D000068878:Trastuzumab