Abstract 3029: MKP1-mediated survival of HER2 positive 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 over-expressed in radio-resistant breast cancer cells that survived long-term fractionated irradiation. Herein, we showed that MKP1 is expressed exclusively in HER2 positive clinical breast tumors compared to HER2 negative tumors. Comparison of normal and tumor breast tissue samples from same patients revealed that MKP1 expression is induced in breast tumors along with HER2 expression in patients, who showed low/no expression of MKP1 and HER2 in their normal breast tissue. Most importantly, we have shown that HER2 positive breast cancer cells rely heavily on MKP1 for survival as knocking down MKP1 resulted in a massive cell death. MKP1 was found to translocate into the mitochondria in breast cancer cells upon radiation and mitochondrial MKP1 levels were significantly enhanced in HER2 over-expressing and radio-resistant breast cancer cells, suggesting a survival mechanism where increased MKP1 translocation into the mitochondria functions to attenuate pro-apoptotic signals initiated from mitochondria-localized MAPK, c-Jun N-terminal kinase (JNK). Consistent with this, increased mitochondr...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Tumor Biology Source Type: research