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

Abstract

The Kru¨ppel-like factor 5 (KLF5) is a zinc-finger transcription factor promoting cell proliferation, cellcycle progression and survival. A high expression level of KLF5 mRNA has been shown to be associated with shorter breast cancer patient survival. However, the mechanism of KLF5 action in breast cancer is still not clear. In this study, we found that both KLF5 and its downstream gene fibroblast growth factor binding protein 1 (FGF-BP) are co-expressed in breast cell lines and primary tumors. Manipulation of the KLF5 expression can positively regulate the FGF-BP mRNA and protein levels in multiple breast cell lines. In addition, the secreted FGF-BP protein in the conditional medium is also regulated by KLF5. Furthermore, we demonstrated that KLF5 binds and activates the FGF-BP promoter through a GC box by luciferase reporter, oligo pull down and chromatin immunoprecipitation (ChIP) assays. When FGF-BP is depleted by siRNA, KLF5 fails to promote cell proliferation in MCF10A, SW527 and TSU-Pr1. We further demonstrated that overexpression or addition of FGF-BP rescues the KLF5-knockdown-induced growth arrest in MCF10A cells. Finally, KLF5 significantly promotes MCF7 breast cancer cell xenograft growth in athymic nude mice. These findings suggest that KLF5 may promote breast cancer cell proliferation at least partially through directly activating the FGF-BP mRNA transcription. Understanding the mechanism of KLF5 action in breast cancer may result in useful diagnostic and therapeutic targets.

Krüppel-like Factor 5 Transcription Factor Promotes Microsomal Prostaglandin E2 Synthase 1 Gene Transcription in Breast Cancer

“…Higher KLF5 mRNA and protein expression is associated with a short survival time in breast cancer patients (33,34). Our previous studies demonstrated that KLF5 promotes MCF7 and HCC1937 breast cancer cell growth in vitro and in vivo (3,35). In this study, we showed several lines of evidence indicating that mPGES1 is a KLF5 direct target gene that partially mediates the pro-proliferative function of KLF5 in breast cancer cells.…”

“…KLF5 expression can be induced by a variety of oncogenic and proinflammatory factors, such as LPS (38), TNF␣ (39), TPA (3,40), and so on. These proinflammatory stimuli also induce mPGES1 (10,17,41).…”

The Fbw7 Tumor Suppressor Targets KLF5 for Ubiquitin-Mediated Degradation and Suppresses Breast Cell Proliferation

“…breast cell lines (17). The KLF5 E3 ligase WWP1 is overexpressed in ERα-positive breast cancer (28).…”

“…KLF5 is highly expressed in estrogen receptor (ER)α-negative basal-type breast cancer and is an unfavorable prognostic biomarker correlated with shorter survival for breast cancer patients (18,19). Our previous studies suggest that KLF5 promotes breast cell proliferation through directly upregulating the FGF-BP gene transcription (17). More recently, inhibition of KLF5 by small interfering RNA (siRNA) using nanoparticles has been shown to efficiently inhibit tumor growth in vivo (20).…”

“…Accumulated evidence suggests that KLF5 promotes fibroblast, colon, bladder, and breast cell proliferation (15)(16)(17). KLF5 is highly expressed in estrogen receptor (ER)α-negative basal-type breast cancer and is an unfavorable prognostic biomarker correlated with shorter survival for breast cancer patients (18,19).…”