Abstract
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.
| Original language | English |
|---|---|
| Journal | Tumor Biology |
| Volume | 34 |
| Issue number | 2 |
| Pages (from-to) | 1161-1170 |
| Number of pages | 10 |
| ISSN | 1010-4283 |
| DOIs | |
| Publication status | Published - Apr 2013 |
Keywords
- 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
