TY - JOUR
T1 - TIMP-1 overexpression does not affect sensitivity to HER2-targeting drugs in the HER2-gene-amplified SK-BR-3 human breast cancer cell line
AU - Deng, Xiaohong
AU - Fogh, Louise
AU - Lademann, Ulrik Axel
AU - Jensen, Vibeke
AU - Stenvang, Jan
AU - Yang, Huanming
AU - Brünner, Nils
AU - Rasmussen, Anne-Sofie Schrohl
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
KW - Antibodies, Monoclonal, Humanized
KW - Antineoplastic Agents
KW - Apoptosis
KW - Blotting, Western
KW - Breast Neoplasms
KW - Cell Proliferation
KW - Drug Resistance, Neoplasm
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - In Situ Hybridization, Fluorescence
KW - PTEN Phosphohydrolase
KW - Phosphorylation
KW - Proto-Oncogene Proteins c-akt
KW - Quinazolines
KW - Receptor, erbB-2
KW - Tissue Inhibitor of Metalloproteinase-1
KW - Tumor Cells, Cultured
U2 - 10.1007/s13277-013-0659-5
DO - 10.1007/s13277-013-0659-5
M3 - Journal article
C2 - 23334956
SN - 1010-4283
VL - 34
SP - 1161
EP - 1170
JO - Tumor Biology
JF - Tumor Biology
IS - 2
ER -
