Kruppel-like transcription factor 5 promotes breast cell survival through pERK-mediated MKP-1 protein stabilization.

Abstract

Abstract Abstract #3019 Kruppel-like Factor 5 (KLF5) is a transcription factor promoting cell survival and tumorigenesis in multiple cancers. High level of KLF5 mRNA is associated with a shorter survival for breast cancer patients. However, the role of KLF5 and mechanism of KLF5 actions in breast cancer remain unclear. In this study, we found that KLF5 knockdown by siRNA in two basal type breast cell lines MCF10A and BT20 induces apoptosis, as indicated by loss of cell viability and cleaved PARP and caspase 3. Interestingly, a survival phosphotase, MKP-1, is downregulated at protein level by KLF5 ablation. Consistently, KLF5 over-expression increases the MKP-1 protein expression. However, MKP-1 is not a KLF5 direct target gene because the MKP-1 mRNA level is not regulated by KLF5. By the cycloheximide chase assays, we found that KLF5 decreases the MKP-1 protein degradation. However, KLF5 does not decrease the MKP-1 E3 ubiquitin ligase SKP2 expression. The ERK inhibitor U0126 specifically blocks the KLF5 induced MKP-1, suggesting that KLF5 up-regulates MKP-1 through activating ERK signaling. Finally, we demonstrated that MKP-1 over-expression blocks KLF5 knockdown induced apoptosis in MCF10A cells. These findings suggest that KLF5 is a survival factor which promotes breast cell survival partially through pERK-mediated MKP-1 stabilization. The KLF5-pERK-MKP-1 signaling axis may provide new therapeutic targets for invasive breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3019.