Tissue inhibitor of metalloproteinases-1 protects the human breast carcinoma cell line MCF-7 S1 against anthracycline-induced cell death by activation of the akt survival pathway.

Abstract

Abstract Abstract #2019 Würtz S and Schrohl A contributed equally.
 Background. A large proportion of breast cancer patients are offered chemotherapy following primary surgery, however, many of these patients do not benefit from the treatment. Currently, only few markers exist to predict whether a breast cancer patient will respond to chemotherapy in general or to specific types of chemotherapy. Thus, additional predictive markers need to be identified to ensure a more effective treatment of the patients. In this regard, recent clinical studies performed in our laboratory have demonstrated that high tumor tissue levels of TIMP-1 are associated with a poor response to the most frequently used chemotherapeutic drugs (CMF or anthracyclines) (Schrohl et al., Clin. Cancer Res. 2006 and Klintman et al. manus. in prep.). The purpose of the present study was to investigate the molecular explanation for the clinical findings concerning the predictive value of TIMP-1 using an in vitro approach.
 Methods. We stably transfected the human breast carcinoma cell line MCF-7 S1 with the human TIMP-1 gene and established single cell clones expressing different levels of TIMP-1. We then compared the sensitivity of these cells to epirubicin and taxol using cell death and apoptosis assay. In addition, we investigated the signalling pathway that could be involved in the TIMP-1 mediated protection against treatment using western blotting of key molecules.
 Results. We found that clones expressing high levels of TIMP-1 were significantly less sensitive to epirubicin. In contrast, no difference in sensitivity to taxol was demonstrated between high and low TIMP-1 clones. When investigating the signalling pathway involved in the difference in sensitivity we found that phosphorylated Akt was highly up-regulated in the high TIMP-1 clones compared to the low TIMP-1 clones following chemotherapeutic treatment.
 Conclusion. TIMP-1 protects the MCF-7 S1 cells against anthracycline-induced cell death but not against taxol. Thus, TIMP-1 may be used to discriminate between patients likely to benefit from anthracyclines and patients who should be offered an alternative drug. Furthermore, we found that this protection is probably executed through counteraction of the apoptotic signal by activation of the Akt survival pathway. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2019.