Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells

Demet Candas, Chung Ling Lu, Ming Fan, Frank Chuang, Colleen A Sweeney, Alexander D Borowsky, Jian-Jian Li

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7498-7509
Number of pages12
JournalCancer Research
Volume74
Issue number24
DOIs
StatePublished - Dec 15 2014

Fingerprint

Breast Neoplasms
Therapeutics
Dual Specificity Phosphatase 1
MAP Kinase Kinase 4
Neoplastic Stem Cells
MAP Kinase Signaling System
Radiation Tolerance
Mitochondrial Membranes
Cell Survival
Mitochondria
Stem Cells
Radiation
Survival
Population
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells. / Candas, Demet; Lu, Chung Ling; Fan, Ming; Chuang, Frank; Sweeney, Colleen A; Borowsky, Alexander D; Li, Jian-Jian.

In: Cancer Research, Vol. 74, No. 24, 15.12.2014, p. 7498-7509.

Research output: Contribution to journalArticle

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