HUMAN DNA TOPOISOMERASE II-ALPHA - A NEW MARKER OF CELL-PROLIFERATIONIN INVASIVE BREAST-CANCER

DNA topoisomerase LI-alpha is the molecular target of doxorubicin, an active drug used in the therapy of breast cancer. From many in vitro s tudies, it is known that high levels of topo II-alpha expression corre late with drug sensitivity, and low levels of topo II-alpha correlate with drug resistance, In addition, the enzyme is known to be a marker of cell proliferation in normal tissues. Because the number of prolife rating cells in a breast cancer has been shown to be prognostically im portant, and because doxorubicin is used in the treatment of breast ca ncer, we hypothesized that the measurement of topo II-alpha in breast cancer may not only give drug sensitivity information but also may yie ld important data on cell proliferation. Ln this study, formalin-fixed , paraffin-embedded tissue from 30 specimens of invasive breast cancer from 20 patients were immunohistochemically stained for topo II-alpha with a mouse monoclonal antibody. For each case, a topo II-alpha inde x was determined that represents the number of positive-staining tumor cells divided by the total number of tumor cells counted times 100., A similar index was determined for MIB1, a known cell proliferation ma rker. Each case was also graded according to the modified Bloom-Richar dson criteria and evaluated for c-erbB-2 amplification, hormonal statu s, S-phase fraction, and mitotic index. The topo II-alpha index correl ates better with the MIB1 index than with the S-phase fraction or mito tic index. The topo II-alpha expression in breast cancer ranges from l ow (topo II-alpha index <1) to high (topo II-alpha index = 86), Amplif ication of c-erbB-2 was observed in 4 of 28 cases (14%) but did not co rrelate with high topo II-alpha indices. We conclude that measurement of topo II-alpha in invasive breast cancer can be readily performed by immunohistochemical staining, and it gives information on the number of cycling tumor cells, In addition, because the enzyme is the molecul ar target of doxorubicin, the expression of the enzyme may relate also to the sensitivity or resistance of the tumor to doxorubicin-based ch emotherapeutic protocols, Copyright (C) 1997 by W.B. Saunders Company.