K-Ras stabilization by estrogen via PKCδ is involved in endometrial tumorigenesis

Estrogens are considered as a major risk factor of endometrial cancer. In this study, we identified a mechanism of tumorigenesis in which K-Ras protein is stabilized via estrogen signaling through the ER-alpha 36 receptor. PKC delta was shown to stabilize K-Ras specifically via estrogen signaling. Estrogens stabilize K-Ras via inhibition of polyubiquitylation-dependent proteasomal degradation. Estrogen-induced cellular transformation was abolished by either K-Ras or PKC delta knockdown. The role of PKC delta in estrogen-induced tumorigenesis was confirmed in a mouse xenograft model by reduction of tumors after treatment with rottlerin, a PKCd inhibitor. Finally, levels of PKC delta correlated with that of Ras in human endometrial tumor tissues. Stabilization of K-Ras by estrogen signaling involving PKC delta up-regulation provides a potential therapeutic approach for treatment of endometrial cancer.