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


METHODS
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.
Pandya
Ashka Y
AY
Department of Cell Biology, University of Alabama at Birmingham, 35294, USA.
Talley
Lynya I
LI
Frost
Andra R
AR
Fitzgerald
Thomas J
TJ
Trivedi
Vivek
V
Chakravarthy
Mithun
M
Chhieng
David C
DC
Grizzle
William E
WE
Engler
Jeffrey A
JA
Krontiras
Helen
H
Bland
Kirby I
KI
LoBuglio
Albert F
AF
Lobo-Ruppert
Susan M
SM
Ruppert
J Michael
JM
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D018572:Disease-Free Survival; D000939:Epitopes / Q000737:chemistry; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D015999:Multivariate Analysis; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012044:Regression Analysis; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D014162:Transfection; D016896:Treatment Outcome; D015854:Up-Regulation
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D000939:Epitopes; C000715467:KLF4 protein, human; D019394:Ki-67 Antigen; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors