A gene on the HER2 amplicon, C35, is an oncogene in breast cancer whose actions are prevented by inhibition of Syk

• Published in: British journal of cancer 2010-07, Vol.103 (3), p.401-410
• Main Authors: Katz, E, Dubois-Marshall, S, Sims, A H, Faratian, D, Li, J, Smith, E S, Quinn, J A, Edward, M, Meehan, R R, Evans, E E, Langdon, S P, Harrison, D J
• Format: Article
• Language: English
• Subjects: 631/208/199; 631/67/1059/602; 631/67/395; 692/699/67/1347; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cadherins - genetics; Cancer Research; Cell culture; Cell Line, Tumor; Colony-Forming Units Assay; Cytokeratin; DNA Primers; Down-Regulation; Drug Resistance; Epidemiology; Female; Gene Amplification; Genes, erbB-2; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Keratin; Kinases; Mammary gland diseases; Medical research; Medical sciences; Molecular Diagnostics; Molecular Medicine; Mutation; Neoplasm Proteins - genetics; Oligonucleotide Array Sequence Analysis; Oncology; Open Reading Frames; Protein expression; Protein-Tyrosine Kinases - antagonists & inhibitors; Proteins; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Syk Kinase; Transfection; Trastuzumab; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605763

Background: C35 is a 12 kDa membrane-anchored protein endogenously over-expressed in many invasive breast cancers. C35 ( C17orf37 ) is located on the HER2 amplicon, between HER2 and GRB7 . The function of over-expressed C35 in invasive breast cancer is unknown. Methods: Tissue microarrays containing 122 primary human breast cancer specimens were used to examine the association of C35 with HER2 expression. Cell lines over-expressing C35 were generated and tested for evidence of cell transformation in vitro . Results: In primary breast cancers high levels of C35 mRNA expression were associated with HER2 gene amplification. High levels of C35 protein expression were associated with hallmarks of transformation, such as, colony growth in soft agar, invasion into collagen matrix and formation of large acinar structures in three-dimensional (3D) cell cultures. The transformed phenotype was also associated with characteristics of epithelial to mesenchymal transition, such as adoption of spindle cell morphology and down-regulation of epithelial markers, such as E-cadherin and keratin-8. Furthermore, C35-induced transformation in 3D cell cultures was dependent on Syk kinase, a downstream mediator of signalling from the immunoreceptor tyrosine-based activation motif, which is present in C35. Conclusion: C35 functions as an oncogene in breast cancer cell lines. Drug targeting of C35 or Syk kinase might be helpful in treating a subset of patients with HER2 -amplified breast cancers.