Topoisomerase IIalpha expression in breast cancer: correlation with outcome variables

Mod Pathol. 2000 May;13(5):542-7. doi: 10.1038/modpathol.3880094.


Topoisomerase IIalpha (topo IIalpha) plays a key role in DNA replication and is a target for multiple chemotherapeutic agents. In breast cancer, topo II expression has been linked to cell proliferation and HER2/neu protein overexpression. However, its relationship with outcome variables is not well established. Formalin-fixed, paraffin-embedded primary breast cancers from 184 women (mean age, 60 years) were stained for topo II by automated immunohistochemistry. A topo II expression index (TI) was determined by counting the number of positive cells per high-power field and calculating an overall mean number of positive cells per high-power field. Tumors with a TI of more than 1 were considered positive, and those with a TI of 1 or less were considered negative. A cell proliferation index was determine d by automated immunohistochemistry using the MIB-1 antibody in an identical technique. HER-2/neu gene amplification (HER-2 amp) was determined by automated fluorescence in situ hybridization using the Ventana unique sequence probe. Fifty-nine (32%) of the tumors had a TI greater than 1. On univariate analysis, increased topo II expression correlated with decreased patient survival (p = .001), advanced tumor stage (p = .034), lymph node metastasis (p = .018), and HER-2 amp (p = .016). Tumor stage (p < .0001), node-positive status (p < .0001), tumor grade (p = .025), HER-2 amp (p < .0001), and MIB-1 overexpression (p = .002) also correlated with survival on univariate analysis. Topo II expression did not correlate with tumor size, grade, estrogen receptor/progesterone receptor status, or disease recurrence. On multivariate analysis, stage (p < .0001), lymph node metastasis (p < .0001), and tumor grade (p = .002) all independently predicted disease-related death. Increased topo II expression is associated with an aggressive form of breast cancer featuring HER-2 amp and predicts disease-related death, lymph node metastasis, and advanced tumor stage.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, Neoplasm
  • Antigens, Nuclear
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / enzymology*
  • Carcinoma, Ductal, Breast / genetics
  • Carcinoma, Ductal, Breast / pathology
  • DNA Topoisomerases, Type II* / biosynthesis*
  • DNA-Binding Proteins
  • Female
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Isoenzymes / biosynthesis*
  • Ki-67 Antigen
  • Lymphatic Metastasis
  • Middle Aged
  • Multivariate Analysis
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Nuclear Proteins / analysis
  • Proportional Hazards Models
  • Receptor, ErbB-2 / genetics
  • Receptors, Estrogen / analysis
  • Receptors, Progesterone / analysis
  • Survival Analysis


  • Antigens, Neoplasm
  • Antigens, Nuclear
  • DNA-Binding Proteins
  • Isoenzymes
  • Ki-67 Antigen
  • Nuclear Proteins
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Receptor, ErbB-2
  • DNA Topoisomerases, Type II