Characterization of a novel cell line established from a patient with Herceptin-resistant breast cancer
Minna Tanner1, Anita I Kapanen, Teemu Junttila
1Laboratory of Cancer Biology, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland.
Abstract:
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.
Insights
A new breast cancer cell line, JIMT-1, resistant to trastuzumab (Herceptin), has been developed. This model aids research into HER-2 targeted therapy resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Drug Resistance
Background:
- Clinical resistance to trastuzumab (Herceptin), a HER-2 oncogene-targeting drug, poses a significant challenge in breast cancer treatment.
- Existing experimental models are insufficient for studying the mechanisms underlying this resistance.
Purpose of the Study:
- To establish and characterize a novel experimental model system for investigating trastuzumab resistance in HER-2 positive breast cancer.
- To provide a tool for understanding the molecular basis of resistance to HER-2 targeted therapies.
Main Methods:
- Established a new carcinoma cell line (JIMT-1) from a patient with trastuzumab-resistant breast cancer.
- Characterized JIMT-1 cells for HER-2 amplification, mutations, receptor expression, and phenotypic markers.
- Assessed sensitivity to trastuzumab, pertuzumab, and small molecule tyrosine kinase inhibitors (Ci1033, ZD1839) in vitro and in vivo.
- Analyzed downstream signaling pathways, including Akt and Erk1/2 phosphorylation.
Main Results:
- The JIMT-1 cell line exhibits HER-2 gene amplification and overexpression without coding sequence mutations.
- JIMT-1 cells are resistant to trastuzumab and pertuzumab in vitro and in xenograft models.
- Growth inhibition by small molecule tyrosine kinase inhibitors was less pronounced compared to sensitive cell lines, linked to unaltered Akt phosphorylation.
- The cell line displays characteristics of epithelial progenitor cells and lacks hormone receptor expression.
Conclusions:
- The JIMT-1 cell line represents a valuable and unique experimental model for studying clinical resistance to HER-2 targeted therapies.
- This model will facilitate the exploration of novel resistance mechanisms and the development of alternative treatment strategies for HER-2 positive breast cancer.
