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¹ Laboratory of Cancer Biology, Institute of Medical Technology, Tampere University and Tampere University Hospital, and ² Department of Oncology, Tampere University Hospital, Tampere, Finland; ³ Medicity Research Laboratories and Department of Medical Biochemistry and Molecular Biology, and ⁴ Turku Graduate School of Biomedical Sciences, University of Turku; and ⁵ University Hospital Turku, Turku,Finland

Requests for reprints: Prof. Jorma Isola, Laboratory of Cancer Biology, Institute of Medical Technology, University of Tampere and Tampere University Hospital, FIN-33014 Tampere, Finland. Phone: 358-3-2156729; Fax: 358-3-2158923. E-mail: jorma.isola{at}uta.fi

Clinical resistance to the HER-2 oncogene–targeting drug trastuzumab (Herceptin) exists, but studies of the resistance mechanisms are hampered by the lack of suitable experimental model systems. We established a carcinoma cell line (designated JIMT-1) from a pleural metastasis of a 62-year old patient with breast cancer who was clinically resistant to trastuzumab. JIMT-1 cells grow as an adherent monolayer and form xenograft tumors in nude mice. JIMT-1 cells have an amplified HER-2 oncogene, which showed no identifiable mutations in its coding sequence. JIMT-1 cells overexpress HER-2 mRNA and protein, and the levels of HER-1, HER-3, and HER-4 mRNA and protein were similar to the trastuzumab-sensitive cell line SKBR-3. The cell line lacks expression of hormone receptors (estrogen receptors and progesterone receptors) and is phenotypically of epithelial progenitor cell origin, as evidenced by immunohistochemical positivity for both cytokeratins 5/14 and 8/18. JIMT-1 cells were insensitive to trastuzumab and another HER-2-inhibiting drug, pertuzumab (2C4), in vitro and in xenograft tumors. Small molecule tyrosine kinase inhibitors Ci1033 and ZD1839 inhibited the JIMT-1 cell growth but to a lesser degree than in trastuzumab-sensitive BT-474 cells. The lack of growth inhibition was rationalized by the unaltered Akt phosphorylation in JIMT-1 cells. Erk1/2 phosphorylation was slightly reduced but still evident in JIMT-1 cells. We conclude that the JIMT-1 cell line provides a valuable experimental model for studies of new trastuzumab-resistance mechanisms.

Key Words: cell line • c-erbB2 • drug resistance • oncogene • trastuzumab

Grant support: European Union Research contract FP5 QLRT-1999-3126 (to the Laboratory of Cancer Biology, Institute of Medical Technology, Tampere University), Tampere University Hospital Research Foundation, Academy of Finland, Sigrid Juselius Foundation, Emil Aaltonen Foundation, and the Finnish Cancer Foundation.

Notes: M. Tanner and A.I. Kapanen contributed equally to this work.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁶ K. Rennstam et al. Cytogenetic characterization and gene expression profiling of the Herceptin-resistant breast cancer cell line JIMT-1, submitted for publication.

⁷ http://www.ensembl.org

Received 6/ 7/04; revised 9/24/04; accepted 10/15/04.