Estrogen Suppresses MLK3-Mediated Apoptosis Sensitivity in ER+ Breast Cancer Cells

Abstract

Little knowledge exists about the mechanisms by which estrogen can impede chemotherapy-induced cell death of breast cancer cells. 17β-Estradiol (E₂) hinders cytotoxic drug–induced cell death in estrogen receptor–positive (ER⁺) breast cancer cells. We noted that the activity of the proapoptotic mixed lineage kinase 3 (MLK3) kinase was relatively higher in estrogen receptor–negative (ER⁻) breast tumors, suggesting that E₂ might inhibit MLK3 activity. The kinase activities of MLK3 and its downstream target, c-Jun NH₂-terminal kinase, were rapidly inhibited by E₂ in ER⁺ but not in ER⁻ cells. Specific knockdown of AKT1/2 prevented MLK3 inhibition by E₂, indicating that AKT mediated this event. Furthermore, MLK3 inhibition by E₂ involved phosphorylation of MLK3 Ser⁶⁷⁴ by AKT, attenuating the proapoptotic function of MLK3. We found that a pan-MLK inhibitor (CEP-11004) limited Taxol-induced cell death and that E₂ accentuated this limitation. Taken together, our findings indicate that E₂ inhibits the proapoptotic function of MLK3 as a mechanism to limit cytotoxic drug–induced death of ER⁺ breast cancer cells. Cancer Res; 70(4); 1731–40