Topoisomerase IIa (alpha) in breast cancer
Järvinen, Tero (1999)
Tampere University Press
Syöpäbiologia - Cancer Biology
Topoisomerase IIa (topoIIa) is a key enzyme in DNA replication and a molecular target for many commonly used anti-cancer drugs called topoII-inhibitors. In vitro-studies have established direct relationship between the response to topoII-inhibitors and topoIIa expression level in cancer cells: cells with low nuclear concentrations of topoIIa are less sensitive to topoII-directed drugs than cells containing high amounts of topoIIa. There are no commonly accepted markers available to predict the response to cytotoxic chemotherapy in breast cancer. I studied whether topoIIa can predict the response to topoII-inhibitors in metastatic breast cancer. TopoIIa expression was found be proliferation-dependent in primary breast cancer: rapidly proliferating cancer cells expressed more topoIIa than cancer cells with low proliferation rate. In addition, high topoIIa expression associated with ErbB2 oncogene overexpression, aneuploidy of the tumor and negative hormone receptor status. The percentage of topoIIa-positive cancer cells could not predict the response to topoII-inhibitor chemotherapy in metastatic breast cancer. Because somatic genetic changes contribute to malignant transformation as well as to cancer progression, topoIIa gene copy number aberrations were studied by fluorescence in situ hybridization (FISH). TopoIIa gene amplifications as well as physical deletions were identified in breast cancer cells lines and primary tumors. TopoIIa gene aberrations were found exclusively with ErbB2 oncogene amplification. About 90% of primary tumors with ErbB2 amplification contained simultaneous topoIIa aberration. TopoIIa amplification was associated with an increase in the expression level of topoIIa in breast cancer cell lines and primary tumors, whereas topoIIa deletion decreased the topoIIa protein expression markedly. These changes in the protein expression, in turn, altered the sensitivity to topoII-inhibitor in vitro. TopoIIa amplification induced hypersensitivity to topoII-inhibitor, while topoIIa deletion caused primary resistance. TopoIIa gene aberrations are both biologically relevent and common in clinical breast cancer. The results obtained in this study encourage to test whether topoIIa can be used as a predictive factor for topoII-inhibitors either in adjuvant or metastatic setting of breast cancer.
- Väitöskirjat