Expression of KLF5 is a Prognostic Factor for Disease-Free Survival and Overall Survival in Patients with Breast Cancer

Abstract

Purpose: Kruppel-like factor (KLF5) is a cell growth mediator in various epithelial cells. Higher KLF5 increases cell growth rate and leads to transformed phenotypes. Because tumor cell proliferation is tightly associated with tumor progression, and consequently, with survival of cancer patients, we wanted to examine the prognostic value of KLF5 gene expression for patients with breast cancer. Experimental Design: The gene expression levels of KLF5, ER, PR, HER2, and MKI67 were quantified in the tumor tissues of 90 patients with breast cancer and correlated with disease-free survival and overall survival of the patients. The correlations of gene expression between KLF5 and ER, PR, HER2, and MKI67 were analyzed. In addition, KLF5 expression was also compared with clinical data and age of patients. Results: Statistically significant correlations were found between gene expression of KLF5 and both disease-free survival (univariate analysis) and overall survival (univariate and multivariate analysis). Patients with higher KLF5 expression had shorter disease-free survival and overall survival time, whereas patients with lower KLF5 expression had better survival. Moreover, KLF5 was also found to be positively correlated with HER2 and MKI67, and negatively correlated with age of the patients at diagnosis. Conclusion: The gene expression of KLF5 is directly correlated with cell proliferation in vivo and is a prognostic factor for patients with breast cancer. Patients with higher KLF5 expression have shorter disease-free survival and overall survival than patients with lower KLF5 expression. In addition, KLF5 has higher expression in patients ages V50 years old than in patients >50 years old.Kruppel-like factor 5 (KLF5), also called intestinal-enriched KLF5, is a DNA-binding transcriptional regulator, and contains three independent peptide modules of the C 2 H 2 zinc finger type (1). KLF5 gene expression is well-regulated in embryos, with a higher level of expression towards the later stage of fetal development. It is widely expressed in human tissues including colon, small intestine, prostate, pancreas, kidney, skeletal muscle, lung, and breast (2 -4). In the intestinal tract, KLF5 expression is concentrated at the base of the crypt epithelium in which active cell division occurs (5).KLF5 has been reported to have growth-promoting effects in cultured cells based on a number of studies. Constitutive expression of KLF5 results in an increased rate of proliferation, and eventually, in a transformed phenotype, as characterized by anchorage-independent growth (6, 7). This regulatory function of KLF5 on cell proliferation might be through the stimulation of cyclin D1 (8), cyclin B1, and Cdc2 gene expression (9), or by mediating the inhibitory effect of retinoids on cell proliferation (7). KLF5 was also shown to regulate the pro-proliferative and transforming activities of oncogenic H-ras. In oncogenic H-rastransformed NIH3T3 cells, an elevated level of KLF5 transcript was shown. The accelerated proliferation and the ...

Krüppel-like factor 5 promotes breast cell proliferation partially through upregulating the transcription of fibroblast growth factor binding protein 1

“…KLF5 has been reported to be an independent prognosis marker in breast cancer because patients with higher KLF5 mRNA expression have shorter survival than patients with lower KLF5 expression (Tong et al, 2006). This observation was further supported by independent microarray studies (Oncomine.org).…”

“…Functionally, both genes promote cell transformation and angiogenesis (Czubayko et al, 1997;Shindo et al, 2002). Finally, both genes have been reported to be overexpressed in breast cancer (Kagan et al, 2003;Tong et al, 2006). However, whether KLF5 directly binds to the FGF-BP promoter, upregulates its transcription and functions through FGF-BP in breast cancer are unknown.…”

“…KLF5 is highly expressed in immortalized breast epithelial cells but lost in many breast cancer cell lines (Chen et al, 2002). However, the high expression level of KLF5 has been shown to be an unfavorable prognostic factor for disease-free survival and overall survival in patients with breast cancer (Tong et al, 2006). In a most recent study (Ben-Porath et al, 2008), KLF5 was reported to be one of the nine genes that are overexpressed in high-grade and poorly differentiated aggressive breast tumors.…”

Up-Regulation of Krüppel-Like Factor 5 in Pancreatic Cancer Is Promoted by Interleukin-1β Signaling and Hypoxia-Inducible Factor-1α

“…Due to the fact that high expression of KLF5 is also observed in breast cancer, we additionally compared KLF5 expression to MCF-7 breast cancer cells and found similar results in terms of a higher expression by pancreatic cancer cells (data not shown; refs. 6,19). Importantly, we found that phosphorylation of MEK did not strongly correlate with KLF5 levels, suggesting that the MEK pathway might not be the critical determinant for KLF5 up-regulation in pancreatic cancer cells (Fig.…”

“…This transcription factor is also known as an intestinal-enriched Krüppel-like factor and is predominantly present in the proliferating crypt epithelial cells of the intestine (5). Nevertheless, controversy persists as to whether this transcription factor functions as a tumor suppressor or as an oncogene because clinical studies have shown that KLF5 overexpression is either associated with a poor prognosis in patients with breast cancer (6) or correlates with improved survival in patients with gastric cancer (7). Moreover, a recent experimental study showed that restoring KLF5 expression in prostate cancer cells reduces tumor growth in preclinical tumor models (8), and one study additionally suggested a metastasis-suppressive action of KLF5 in TE2 esophageal carcinoma cells (9).…”