EXPRESSION OF TOPOISOMERASE II-ALPHA IS ASSOCIATED WITH RAPID CELL-PROLIFERATION, ANEUPLOIDY, AND C-ERBB2 OVEREXPRESSION IN BREAST-CANCER

The role of molecular markers predicting the response to cytotoxic che motherapy is not established, A potential predictive factor, topoisome rase II alpha (topo II alpha), is a target for certain cytotoxic drugs , and its concentration has been shown to correlate with chemosensitiv ity in vitro. We evaluated expression of topo II alpha immunohistochem ically in 230 breast cancer samples and studied its association with k nown clinicopathological factors and factors previously shown to predi ct response to cytotoxic drugs, Topo II alpha protein expression was f ound in 0.6 to 33.4% (10.6 +/- 7.9%, mean +/- SD) of breast carcinoma cells, whereas expression was undetectable in nonmalignant breast epit helium. Topo II alpha protein expression correlated well with semiquan titative mRNA in situ hybridization (P = 0.007). A significant associa tion was found between the proportion of topo-II alpha-positive cells and low estrogen and progesterone receptor content (P < 0.0001), high grade (P < 0.0001), DNA aneuploidy (P = 0.003), and c-erbB-2 oncoprote in overexpression (P < 0.0001). Topo II(alpha expression was not assoc iated with clinical variables, such as age of the patient, primary tum or size, or axillary nodal status. A highly significant linear correla tion teas found between topo II alpha and tumor proliferation rate (S- phase fraction, r = 0.46 P < 0.0001). Because hormone receptors, grade , and ploidy are associated with tumor proliferation rate, topo II alp ha expression was adjusted for S-phase fraction to reveal the prolifer ation-independent clinopathological associations. According to the ana lysis of co-variance, only aneuploidy (P = 0.0003) and c-erbB-2 overex pression (P = 0.01) were associated with proliferation-adjusted expres sion of topo II alpha. In conclusions, the close association of Topo I I alpha with Other potential predictive factors (tumor proliferation r ate, c-erbB-2 oncoprotein) suggests that topo II alpha, having a defin ed role as a target for cytotoxic drags, may be a valunble predictor o f response to chemotherapy.