TIMP-1 overexpression does not affect sensitivity to HER2-targeting drugs in the HER2-gene-amplified SK-BR-3 human breast cancer cell line
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Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been suggested as a marker of prognosis and response to treatment in breast cancer. In vitro, TIMP-1 can regulate shedding of the extracellular domain of HER2 and signalling via the Akt pathway, and we hypothesize that TIMP-1 therefore can affect sensitivity to the HER2-targeting drugs trastuzumab and lapatinib. SK-BR-3 human breast cancer cells were stably transfected with TIMP-1, characterized with regard to TIMP-1 protein expression, proliferation, and functionality of the secreted TIMP-1, and the sensitivity to trastuzumab and lapatinib was studied in five selected single-cell subclones expressing TIMP-1 protein at various levels plus the parental SK-BR-3 cell line. Both trastuzumab and lapatinib reduced cell viability, as determined by MTT assay, but the sensitivity to the drugs was not associated with the expression level of TIMP-1 protein. Western blotting showed that the activation of Akt, PTEN, and HER2 as well as ADAM10 was similar in all clones. In conclusion, in this model, TIMP-1 overexpression does not affect HER2 cleavage by ADAM10 or signalling via the Akt pathway, and TIMP-1 does not influence sensitivity to trastuzumab and lapatinib.
|Number of pages||10|
|Publication status||Published - 2013|
- Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Apoptosis, Blotting, Western, Breast Neoplasms, Cell Proliferation, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, In Situ Hybridization, Fluorescence, PTEN Phosphohydrolase, Phosphorylation, Proto-Oncogene Proteins c-akt, Quinazolines, Receptor, erbB-2, Tissue Inhibitor of Metalloproteinase-1, Tumor Cells, Cultured