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

Kruppel-like factor 4 (KLF4) is a transcription factor that participates in both tumor suppression and oncogenesis. To determine the association of KLF4 with tumorigenesis, we integrated data assembled in the Oncomine database and discovered a decrease in KLF4 gene transcripts in breast cancers. Further analysis of the database also showed a correlation between KLF4 expression and estrogen receptor-alpha (ER alpha) positivity. Knockdown of KLF4 in MCF-7 cells elevated the growth rate of these cells in the presence of estrogen. Therefore, we examined the interaction between KLF4 and ER alpha, and found that KLF4 bound to the DNA-binding region of ER alpha. KLF4 thus inhibits the binding of ER alpha to estrogen response elements in promoter regions, resulting in a reduction in ER alpha target gene transcription. Earlier studies have reported that KLF4 is transcriptionally activated by p53 following DNA damage. We also showed that activation of p53 decreased the transcriptional activity of ER alpha by elevating KLF4 expression. Our studies discovered a novel molecular network between p53, KLF4 and ER alpha. As both p53 and ER alpha are involved in cell growth and apoptosis, these results may explain why KLF4 possesses both tumor suppressive and oncogenic functions in breast cancers. Oncogene (2009) 28, 2894-2902; doi:10.1038/onc.2009.151; published online 8 June 2009