Abstract 74: Mitochondrial MKP1-mediated radioresistance in breast cancer stem cells.

The overall cure rate of primary tumors has been significantly improved in the last three decades; however, metastatic and recurrent tumors with aggressive growth and therapy-resistance remain as the major factors shortening breast cancer patients’ survival. MKP1, a mitogen-activated protein kinase (MAPK) phosphatase, was shown to be linked with chemoresistance in breast cancer cells and was overexpressed in radioresistant breast cancer cells that survived long-term fractionated irradiation. Herein, we showed that MKP1 is present in the mitochondria and mitochondrial MKP1 levels are significantly enhanced in irradiated cells, suggesting that increased MKP1 translocation into the mitochondria may function to attenuate pro-apoptotic signals that were initiated from mitochondria-localized MAPK, c-Jun N-terminal kinase (JNK). We found that increased mitochondrial MKP1 levels correlated with the reduced level of phosphorylated active JNK in irradiated cells. Such mitochondrial MKP1-mediated dephosphorylation of JNK was predominantly enhanced in the radioresistant breast cancer cells that can be sensitized by siRNA-mediated inhibition of MKP1. Our results also demonstrated the involvement of extracellular regulated kinase (ERK) as the upstream signal for MKP1 mitochondrial translocation. The identification of cancer stem cells (CSCs) in all human tumors and their involvement in tumor radioresistance encouraged the studies investigating whether MKP1-mediated survival mechanism is present in radioresistant breast cancer cells. Here we showed that MKP1 is overexpressed in irradiated HER2-positive breast CSCs. These data provide critical insights on the aggressive phenotype of breast tumors and define novel diagnostic and therapeutic targets to re-sensitize resistant breast cancer stem cells. Citation Format: Demet Candas, Frank Chuang, Ming Fan, Rulong Shen, Colleen Sweeney, Alexander Borowsky, Andrew Vaughan, Jian Jian Li. Mitochondrial MKP1-mediated radioresistance in breast cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 74. doi:10.1158/1538-7445.AM2013-74