Expression of topoisomerase IIalpha is associated with rapid cell proliferation, aneuploidy, and c-erbB2 overexpression in breast cancer.

The role of molecular markers predicting the response to cytotoxic chemotherapy is not established. A potential predictive factor, topoisomerase IIalpha, is a target for certain cytotoxic drugs, and its concentration has been shown to correlate with chemosensitivity in vitro. We evaluated expression of topo IIalpha immunohistochemically in 230 breast cancer samples and studied its association with known clinicopathological factors and factors previously shown to predict response to cytotoxic drugs. Topo IIalpha protein expression was found in 0.6 to 39.4% (10.6 +/- 7.9%, mean +/- SD) of breast carcinoma cells, whereas expression was undetectable in nonmalignant breast epithelium. Topo IIalpha protein expression correlated well with semi-quantitative mRNA in situ hybridization (P = 0.007). A significant association was found between the proportion of topo-IIalpha-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 oncoprotein overexpression (P<0.0001). Topo IIalpha expression was not associated with clinical variables, such as age of the patient, primary tumor size, or axillary nodal status. A highly significant linear correlation was found between topo IIalpha 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 IIalpha expression was adjusted for S-phase fraction to reveal the proliferation-independent clinopathological associations. According to the analysis of co-variance, only aneuploidy (P=0.0003) and c-erb-2 overexpression (P=0.01) were associated with proliferation-adjusted expression of topo IIalpha. In conclusion, the close association of Topo IIalpha with other potential predictive factors (tumor proliferation rate, c-erbB-2 oncoprotein) suggests that topo IIalpha, having a defined role as a target for cytotoxic drugs, may be a valuable predictor of response to chemotherapy.