Mitochondrial MKP1 Is a Target for Therapy-Resistant HER2-Positive Breast Cancer Cells

Autor: Demet Candas, Jian Jian Li, Ming Fan, Chung-Ling Lu, Alexander D. Borowsky, Frank Y. S. Chuang, Colleen A Sweeney
Rok vydání: 2014
Předmět:
Cancer Research
Pathology
Receptor
ErbB-2
MAP Kinase Kinase 4
Cell
Drug Resistance
Apoptosis
Mitochondrion
Radiation Tolerance
ErbB-2
Stem Cell Research - Nonembryonic - Human
skin and connective tissue diseases
Inner mitochondrial membrane
Cancer
Membrane Potential
Mitochondrial
biology
Mitochondria
Mitochondrial
Gene Expression Regulation
Neoplastic
Protein Transport
Cell killing
medicine.anatomical_structure
Oncology
MCF-7 Cells
Female
Receptor
medicine.medical_specialty
Oncology and Carcinogenesis
Breast Neoplasms
Membrane Potential
Article
Breast cancer
Radioresistance
Breast Cancer
medicine
Humans
Oncology & Carcinogenesis
Radiosensitivity
Neoplastic
CD44
Dual Specificity Phosphatase 1
HCT116 Cells
Stem Cell Research
medicine.disease
Gene Expression Regulation
Drug Resistance
Neoplasm
biology.protein
Cancer research
Neoplasm
Zdroj: Cancer research, vol 74, iss 24
Candas, D; Lu, CL; Fan, M; Chuang, FYS; Sweeney, C; Borowsky, AD; et al.(2014). Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells. Cancer Research, 74(24), 7498-7509. doi: 10.1158/0008-5472.CAN-14-0844. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/2f58t591
ISSN: 1538-7445
0008-5472
Popis: 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. Cancer Res; 74(24); 7498–509. ©2014 AACR.
Databáze: OpenAIRE
Externí odkaz: