Krupple-like factor 5 promotes breast cancer proliferation through activating fibroblast growth factor-binding protein transcription.

Abstract

Abstract Abstract #4071 Breast cancer is the second leading cause of cancer death in U.S. women. The estrogen receptor negative basal breast cancer is usually invasive and the prognosis is poor. Kruppel-like Factor 5 (KLF5) is a zinc-finger transcription factor promoting cell proliferation, survival, cell cycle, and angiogenesis. High expression level of KLF5 has been shown to be associated with shorter breast cancer patient survival time. In our previous microarray studies, fibroblast growth factor binding protein (FGF-BP) is suggested to be one of the KLF5's downstream target genes in the TSU-Pr1 bladder cancer cell line. FGF-BP has been appreciated to be overexpressed in breast tumors and promotes tumorigenesis. To test whether KLF5 promotes cell proliferation through inducing FGF-BP gene transcription in breast cells, we first examined the KLF5 and FGF-BP protein levels in a panel of breast cell lines and found that KLF5 and FGF-BP are co-expressed in ER-negative basal breast cell lines. Over-expression of KLF5 by adenovirus dramatically increased the FGF-BP mRNA and protein expression in MCF7 and BT474. In contrast, KLF5 knockdown decreased the FGF-BP mRNA and protein expression in HCC1937, BT20, and SW527. Importantly, we found that FGF-BP, like KLF5, promotes cell proliferation in MCF10A, SW527 and TSU-Pr1 cells by H3-thymidine incorporation assay. Furthermore, we demonstrated that KLF5 activates the FGF-BP promoter through a putative KLF5 binding site by luciferase reporter assays. We further showed that KLF5 binds to the FGF-BP promoter in vitro by oligo pull down assays and in vivo by chromatin immunoprecipetation (CHIP) assays. These findings suggest that KLF5 may promote breast cancer cell proliferation through directly activating the FGF-BP mRNA transcription. This study will yield valuable insights into the mechanism of KLF5 induced cancer pathogenesis, and will result in useful diagnostic and therapeutic targets. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4071.