Nuclear Localization of KLF4 Is Associated with an Aggressive Phenotype in Early-Stage Breast Cancer

Abstract

Purpose: The Krü ppel-like transcription factor KLF4/ GKLF induces both malignant transformation and a slowgrowth 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 earlystage cancer and small primary tumors (i.e., <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.

KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERα

“…Representative results of two independent data sets characterized by large population sizes (Miller et al, 2005;Ivshina et al, 2006;Richardson et al, 2006;Finak et al, 2008) are shown in Figure 1a (KLF4 expression levels in normal versus breast carcinoma; P ¼ 5.4EÀ4, 7.0EÀ3) and 1b (KLF4 expression levels in breast cancers classified by grade; P ¼ 8.0EÀ11, 2.6EÀ10). Earlier reports have shown that 70% of breast carcinomas have elevated KLF4 expression and that increased nuclear staining for KLF4 is associated with a more aggressive phenotype (Foster et al, 2000;Pandya et al, 2004). Inconsistencies between the results obtained from the Oncomine database and earlier reports may be due to the genetic or epigenetic context of breast cancer tissues.…”

KLF4, p21 and context-dependent opposing forces in cancer

“…KLF4 overexpression becomes evident at the stage of ductal carcinoma in situ, indicating that, similar to squamous cell carcinoma, this represents an early event in breast cancer progression 59 . Furthermore, nuclear localization of KLF4 was found to be a predictor of poor outcome of breast cancer 60 . In contrast to many other cancer types, TP53 is often not mutated in sporadic breast cancer.…”

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Current studies in carcinogen-esis have revealed that KLF4 can function as both tumor promoter and tumor suppressor depending on tissue type and cellular context [241]. The oncogenic effect of KLF4 has been reported in breast and squamous cell carcinoma [243][244][245][246][247], while its tumor suppression role was reported in various types of cancers such as colon cancer [248,249]. It was demonstrated that KLF4 is a fast turnover protein, whose turnover-half life is governed by the ubiquitin-proteasome system [250,251].…”