Tumor resistance, recurrence and metastasis are the primary causes of the failure of cancer treatments. Although extensively studied, the fundamental mechanism underlying the aggressive therapy-resistant tumor phenotype remains to be a major challenge in improving overall cancer cure rate. NF-kB-mediated pro-survival networks are shown to be important mediators of increased survival and radioresistance in breast cancer cells that survive a long- term fractionated irradiation. Recent new evidence further indicate that NF-kB-induces the expression of MAPK phosphatase 1 (MKP1) that is capable of inhibiting apoptosis by attenuating mitochondria-mediated apoptosis in radiation-resistant breast cancer cells. Data provided in this proposal indicate that MKP1 locates in the mitochondria and radiation enhances its mitochondrial influx resulting in the reduction of its substrate JNK phosphorylation, a key event in mitochondria-mediated apoptosis. In addition, breast cancer + -/low stem cells (CSCs with CD44 /CD24) have been identified to be radioresistant and enriched in the surviving fraction of breast cancer cells irradiated with fractionated irradiation. In this study, we propose to elucidate the signaling network of MKP1-mediated anti- mitochondrial apoptosis response in radiation-derived radioresistant breast cancer cell lines. We will investigate whether MKP1-mediated anti-apoptotic response is specifically activated in breast cancer stem cells that are believed to be radioresistant and enriched in the recurrent and metastatic tumor of cancer patients. The hypothesis to be tested is that MKP1- mitochondrial translocation inhibits mitochondrial JNK activity and mitochondria-dependent apoptosis in radioresistant breast CSCs. There are Three Specific Aims: 1, Test whether mitochondrial translocation of MKP1 is responsible for tumor radioresistance;2, Elucidate the molecular mechanisms upstream of MKP1 activation leading to the inhibition of apoptosis;and 3, Detect ERK/MKP1-mediated pro-survival response in radioresistant + -/low CD44 /CD24 breast cancer stem cells in recurrent/metastatic tumors.
Identification of MKP1-mediated radioresistant pathway in breast cancer cells, especially revealing the mechanism of radioresistant breast cancer stem cells, will provide important information in therapy-associated tumor resistance and invent next generation of anti-cancer agents for therapy-resistant breast cancer cells in the recurrent and metastatic tumors.
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