Human Cancer Biology Activation of NF-kB Is a Novel Target of KRAS-Induced Endometrial Carcinogenesis

Purpose: Although the KRAS mutation is one of critical genetic alterations in endometrial carcinogenesis, the downstream targets are not known. Experimental Design: In this study, we investigated the molecular targets of KRAS signals, using tumorigenic cells with oncogenic KRASmutation established from telomerase reverse transcriptase (TERT)immortalized endometrial epithelial cells. Results: We first confirmed that the RAF-ERK pathway, but not the PI3K-Akt pathway, was activated in KRAS tumorigenic cells. However, the introduction of constitutively active MAP/ERK kinase into immortalized cells to mimic RAF-ERK activation failed to obtain tumorigenic phenotypes, indicating the existence of other carcinogenic pathways triggered by KRAS. Recent evidence suggestive of linkage with KRAS signals prompted us to examine the involvement of NF-kB in endometrial carcinogenesis. We found that the DNAbinding activity of NF-kB was markedly elevated in KRAS tumorigenic cells compared with TERTimmortalized cells. Furthermore, the ability of NF-kB to activate the target gene promoters significantly increased in KRAS tumorigenic cells. Introduction of a mutant IkB that is resistant to degradation and thereby enhances the inhibitory effect on NF-kB largely abrogated the transformed phenotypes of KRAS tumorigenic cells. Thus, oncogenic KRAS signals contributed to the tumorigenic phenotypes of endometrial cells by activating the transcription function of NF-kB. Conclusions: These findings clearly show that NF-kB activation is a novel target of oncogenic KRAS in endometrial carcinogenesis, implying the potential utility of NF-kB inhibitors for endometrial cancer chemoprevention, especially with KRAS mutation. Clin Cancer Res; 17(6); 1341–50. 2011 AACR.