Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells.
The MAPK phosphatase MKP1 (DUSP1) is overexpressed in many human cancers, including chemoresistant and radioresistant breast cancer cells, but its functional contributions in these settings are unclear. Here, we report that after cell irradiation, MKP1 translocates into mitochondria, where it prevents apoptotic induction by limiting accumulation of phosphorylated active forms of the stress kinase JNK. Increased levels of mitochondrial MKP1 after irradiation occurred in the mitochondrial inner membrane space. Notably, cell survival regulated by mitochondrial MKP1 was responsible for conferring radioresistance in HER2-overexpressing breast cancer cells, due to the fact that MKP1 serves as a major downstream effector in the HER2-activated RAF-MEK-ERK pathway. Clinically, we documented MKP1 expression exclusively in HER2-positive breast tumors, relative to normal adjacent tissue from the same patients. MKP1 overexpression was also detected in irradiated HER2-positive breast cancer stem-like cells (HER2(+)/CD44(+)/CD24(-/low)) isolated from a radioresistant breast cancer cell population after long-term radiation treatment. MKP1 silencing reduced clonogenic survival and enhanced radiosensitivity in these stem-like cells. Combined inhibition of MKP1 and HER2 enhanced cell killing in breast cancer. Together, our findings identify a new mechanism of resistance in breast tumors and reveal MKP1 as a novel therapeutic target for radiosensitization.
Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.
Demet
D
Candas
Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.
Chung-Ling
CL
Lu
Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.
Ming
M
Fan
Center for Biophotonics, Science and Technology, University of California Davis School of Medicine, Sacramento, California. Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, California.
Frank Y S
FY
Chuang
Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Sacramento, California.
Colleen
C
Sweeney
Center for Comparative Medicine, University of California Davis School of Medicine, Sacramento, California.
Alexander D
AD
Borowsky
Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California. NCI-designated Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, California. jijli@ucdavis.edu.
Jian Jian
JJ
Li
D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000528:radiation effects; D008928:Mitochondria / Q000235:genetics / Q000528:radiation effects; D021381:Protein Transport / Q000528:radiation effects; D011836:Radiation Tolerance / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*
D054638:Dual Specificity Phosphatase 1; D048670:MAP Kinase Kinase 4; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C517019:DUSP1 protein, human