Topoisomerase II Alpha Expression and the Ki-67 Labeling Index Correlate With Prognostic Factors in Estrogen Receptor-Positive and Human Epidermal Growth Factor type-2-negative Breast Cancer

Breast Cancer. 2012 Oct;19(4):309-14. doi: 10.1007/s12282-011-0291-4. Epub 2011 Jul 2.


Background: Topoisomerase II alpha (Topo IIa) is involved in DNA replication and is a molecular target for anthracycline-based chemotherapy. The Ki-67 labeling index (LI) is an evaluation of tumor cell proliferation. The objective of this study was to evaluate relationships among Topo IIa expression, the Ki-67 LI, and prognostic factors in estrogen receptor (ER)-positive, human epidermal growth factor type-2 (HER2)-negative breast cancer.

Materials and methods: Seventy-one patients were diagnosed with ER-positive, HER2-negative breast cancer between July 2003 and December 2004. Formalin-fixed, paraffin-embedded tumor specimens were stained for Topo IIa expression and Ki-67 LI. We investigated the correlation of the level of Topo IIa expression and the Ki-67 LI with clinical factors such as age, tumor size, progesterone receptor status, nodal status, nuclear grade, and lymphovascular invasion (LVI).

Results: Statistically significant differences were observed between Topo IIa overexpression, nuclear grade (p = 0.036), and LVI (p = 0.029). Topo IIa overexpression was statistically correlated with the Ki-67 LI (p < 0.0001). A statistically significant difference was observed between the Ki-67 LI and nuclear grade (p = 0.01). Survival analysis revealed the significant prognostic value of Ki-67 LI in patients with ER-positive, HER2-negative breast cancer (p = 0.003).

Conclusions: Ki-67 LI is a strong prognostic factor in ER-positive HER2-negative breast cancer. Topo IIa overexpression was significantly correlated with the Ki-67 LI, nuclear grade, and LVI. These findings suggest use of Topo IIa expression as a proliferation marker and a prognostic factor in ER-positive, HER2-negative breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anthracyclines / therapeutic use
  • Antigens, Neoplasm / analysis
  • Antigens, Neoplasm / metabolism*
  • Biomarkers, Tumor / analysis
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology*
  • DNA Topoisomerases, Type II / analysis
  • DNA Topoisomerases, Type II / metabolism*
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / metabolism*
  • Female
  • Humans
  • Ki-67 Antigen / analysis
  • Ki-67 Antigen / metabolism*
  • Middle Aged
  • Predictive Value of Tests
  • Prognosis
  • Receptor, ErbB-2 / metabolism*
  • Receptors, Estrogen / metabolism*
  • Receptors, Progesterone / metabolism
  • Retrospective Studies


  • Anthracyclines
  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Ki-67 Antigen
  • Receptors, Estrogen
  • Receptors, Progesterone
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • DNA Topoisomerases, Type II