Järvinen T A, Kononen J, Pelto-Huikko M, Isola J
Laboratory of Cancer Genetics, University of Tampere, Tampere, Finland.
Am J Pathol. 1996 Jun;148(6):2073-82.
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.
预测细胞毒性化疗反应的分子标志物的作用尚未明确。一种潜在的预测因子——拓扑异构酶IIα，是某些细胞毒性药物的作用靶点，其浓度已被证明与体外化疗敏感性相关。我们采用免疫组织化学方法评估了230例乳腺癌样本中拓扑异构酶IIα的表达情况，并研究了其与已知临床病理因素以及先前已证明可预测细胞毒性药物反应的因素之间的关联。在0.6%至39.4%（平均±标准差为10.6±7.9%）的乳腺癌细胞中发现了拓扑异构酶IIα蛋白表达，而在非恶性乳腺上皮中未检测到该表达。拓扑异构酶IIα蛋白表达与半定量mRNA原位杂交结果相关性良好（P = 0.007）。在拓扑异构酶IIα阳性细胞比例与低雌激素和孕激素受体含量（P<0.0001）、高级别（P<0.0001）、DNA非整倍体（P = 0.003）以及c-erbB-2癌蛋白过表达（P<0.0001）之间发现了显著关联。拓扑异构酶IIα表达与患者年龄、原发肿瘤大小或腋窝淋巴结状态等临床变量无关。在拓扑异构酶IIα与肿瘤增殖率（S期分数，r = 0.46；P<0.0001）之间发现了高度显著的线性相关性。由于激素受体、分级和倍性与肿瘤增殖率相关，因此对拓扑异构酶IIα表达进行S期分数校正，以揭示与增殖无关的临床病理关联。根据协方差分析，只有非整倍体（P = 0.0003）和c-erb-2过表达（P = 0.01）与拓扑异构酶IIα的增殖校正表达相关。总之，拓扑异构酶IIα与其他潜在预测因子（肿瘤增殖率、c-erbB-2癌蛋白）的密切关联表明，拓扑异构酶IIα作为细胞毒性药物确定的作用靶点，可能是化疗反应的有价值预测指标。
