Tanner Minna, Kapanen Anita I, Junttila Teemu, Raheem Olayinka, Grenman Seija, Elo Jussi, Elenius Klaus, Isola Jorma
Laboratory of Cancer Biology, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland.
Mol Cancer Ther. 2004 Dec;3(12):1585-92.
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.
对靶向HER-2致癌基因的药物曲妥珠单抗（赫赛汀）存在临床耐药性，但由于缺乏合适的实验模型系统，对耐药机制的研究受到阻碍。我们从一名对曲妥珠单抗临床耐药的62岁乳腺癌患者的胸膜转移灶中建立了一种癌细胞系（命名为JIMT-1）。JIMT-1细胞以贴壁单层形式生长，并在裸鼠体内形成异种移植瘤。JIMT-1细胞具有扩增的HER-2致癌基因，其编码序列未发现可识别的突变。JIMT-1细胞过表达HER-2 mRNA和蛋白，HER-1、HER-3和HER-4 mRNA及蛋白水平与曲妥珠单抗敏感细胞系SKBR-3相似。该细胞系缺乏激素受体（雌激素受体和孕激素受体）的表达，免疫组化显示细胞角蛋白5/14和8/18均呈阳性，表明其表型来源于上皮祖细胞。JIMT-1细胞在体外和异种移植瘤中对曲妥珠单抗和另一种HER-2抑制药物帕妥珠单抗（2C4）均不敏感。小分子酪氨酸激酶抑制剂Ci1033和ZD1839可抑制JIMT-1细胞生长，但抑制程度低于曲妥珠单抗敏感的BT-474细胞。JIMT-1细胞中Akt磷酸化未改变，这解释了其缺乏生长抑制的原因。JIMT-1细胞中Erk1/2磷酸化略有降低但仍很明显。我们得出结论，JIMT-1细胞系为研究新的曲妥珠单抗耐药机制提供了一个有价值的实验模型。
