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

Demet Candas1, Chung-Ling Lu1, Ming Fan1

  • 1Department of Radiation Oncology, University of California Davis School of Medicine, Sacramento, California.

Cancer Research
|November 8, 2014
PubMed

Insights

The MAPK phosphatase MKP1 (DUSP1) moves to mitochondria after radiation, protecting cancer cells from apoptosis and conferring radioresistance, particularly in HER2-positive breast cancer. Targeting MKP1 may enhance radiation therapy effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Mitogen-activated protein kinase phosphatase 1 (MKP1/DUSP1) is overexpressed in various cancers, including chemo- and radioresistant breast cancer.
  • The precise role of MKP1 in cancer cell resistance to radiation therapy remains largely undetermined.

Purpose of the Study:

  • To investigate the functional role of MKP1 in mediating radioresistance in breast cancer cells.
  • To identify MKP1 as a potential therapeutic target for enhancing radiosensitivity.

Main Methods:

  • Examined MKP1 localization and function in irradiated breast cancer cells, focusing on mitochondrial translocation and its effect on JNK signaling.
  • Assessed the impact of MKP1 silencing and combined MKP1/HER2 inhibition on cell survival and radiosensitivity in HER2-positive breast cancer models, including cancer stem-like cells.

Main Results:

  • Following irradiation, MKP1 translocates to the mitochondrial inner membrane space, inhibiting JNK phosphorylation and preventing apoptosis.
  • Mitochondrial MKP1 confers radioresistance in HER2-overexpressing breast cancer cells by acting as a downstream effector of the HER2-activated RAF-MEK-ERK pathway.
  • MKP1 expression is elevated in HER2-positive breast tumors and radioresistant cancer stem-like cells; MKP1 silencing enhances radiosensitivity, and combined inhibition of MKP1 and HER2 increases cell killing.

Conclusions:

  • MKP1 plays a critical role in mitochondrial-mediated radioresistance in HER2-positive breast cancer.
  • MKP1 represents a novel therapeutic target for overcoming resistance and improving the efficacy of radiation therapy in breast cancer.

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