Nuclear localization of KLF4 is associated with an aggressive phenotype in early-stage breast cancer.

Academic Article

Abstract

  • PURPOSE: The Kr├╝ppel-like transcription factor KLF4/GKLF induces both malignant transformation and a slow-growth phenotype in vitro. Although KLF4 expression is increased in most cases of breast cancer, it was unknown whether these cases represent a distinct subtype with a different clinical outcome. EXPERIMENTAL DESIGN: We examined expression of KLF4 by immunostaining 146 cases of human primary infiltrating ductal carcinoma of the breast. Staining patterns were correlated with clinical outcome and with established prognostic factors. RESULTS: Subcellular localization exhibited case-to-case variation. Tumors with high nuclear staining and low cytoplasmic staining were termed type 1. For patients with early-stage disease (i.e., stage I or IIA), type 1 staining was associated with eventual death because of breast cancer (hazard ratio, 2.8; 95% confidence interval, 1.23-6.58; P = 0.011). The association was stronger in patients with early-stage cancer and small primary tumors (i.e., < or =2.0 cm in diameter; hazard ratio, 4.3; 95% confidence interval, 1.75-10.62; P < 0.001). For patients with early-stage disease, multivariate analysis indicated that type 1 staining was independently associated with outcome (adjusted hazard ratio 2.6; 95% confidence interval, 1.10-6.05; P = 0.029). Type 1 staining was also associated with high histological grade (P = 0.032), increased expression of Ki67 (P = 0.016), and reduced expression of BCL2 (P = 0.032). In vitro, KLF4 was localized within the nucleus of transformed RK3E epithelial cells, consistent with a nuclear function of this transcription factor during induction of malignant transformation. CONCLUSIONS: The results suggest that localization of KLF4 in the nucleus of breast cancer cells is a prognostic factor and identify KLF4 as a marker of an aggressive phenotype in early-stage infiltrating ductal carcinoma.
  • Published In

    Keywords

  • Breast Neoplasms, Carcinoma, Ductal, Breast, Cell Line, Cell Line, Transformed, Cell Line, Tumor, Cell Nucleus, Cell Transformation, Neoplastic, Cytoplasm, Cytosol, DNA, Complementary, DNA-Binding Proteins, Disease-Free Survival, Epitopes, Female, Humans, Immunohistochemistry, Ki-67 Antigen, Kruppel-Like Transcription Factors, Multivariate Analysis, Phenotype, Plasmids, Prognosis, Proportional Hazards Models, Proto-Oncogene Proteins c-bcl-2, Regression Analysis, Time Factors, Transcription Factors, Transfection, Treatment Outcome, Up-Regulation
  • Author List

  • Pandya AY; Talley LI; Frost AR; Fitzgerald TJ; Trivedi V; Chakravarthy M; Chhieng DC; Grizzle WE; Engler JA; Krontiras H
  • Start Page

  • 2709
  • End Page

  • 2719
  • Volume

  • 10
  • Issue

  • 8