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Abstract

PURPOSE:

While effective targeted therapies exist for estrogen receptor-positive and HER2-positive breast cancer, no such effective therapies exist for triple-negative breast cancer (TNBC); thus, it is clear that additional targets for radiosensitization and treatment are critically needed.

EXPERIMENTAL DESIGN:

Expression microarrays, qRT-PCR, and Western blotting were used to assess MELK RNA and protein expression levels. Clonogenic survival assays were used to quantitate the radiosensitivity of cell lines at baseline and after MELK inhibition. The effect of MELK knockdown on DNA damage repair kinetics was determined using γH2AX staining. The in vivo effect of MELK knockdown on radiosensitivity was performed using mouse xenograft models. Kaplan-Meier analysis was used to estimate local control and survival information, and a Cox proportional hazards model was constructed to identify potential factors impacting local recurrence-free survival.

RESULTS:

MELK expression is significantly elevated in breast cancer tissues compared with normal tissue as well as in TNBC compared with non-TNBC. MELK RNA and protein expression is significantly correlated with radioresistance in breast cancer cell lines. Inhibition of MELK (genetically and pharmacologically) induces radiation sensitivity in vitro and significantly delayed tumor growth in vivo in multiple models. Kaplan-Meier survival and multivariable analyses identify increasing MELK expression as being the strongest predictor of radioresistance and increased local recurrence in multiple independent datasets.

CONCLUSIONS:

Here, we identify MELK as a potential biomarker of radioresistance and target for radiosensitization in TNBC. Our results support the rationale for developing clinical strategies to inhibit MELK as a novel target in TNBC. ​ 

Author information​

Speers C1, Zhao SG2, Kothari V2, Santola A2, Liu M2, Wilder-Romans K2, Evans J2, Batra N3, Bartelink H4, Hayes DF5,6, Lawrence TS2,6, Brown PH3, Pierce LJ2, Feng FY2,6,7.

1Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. cspeers@umich.edu.

2Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.

3Department of Cancer Prevention, MD Anderson Cancer Center, Houston, Texas.

4Netherlands Cancer Institute, Amsterdam, the Netherlands.

5Clinical Director, Breast Oncology Program, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.

6Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.

7Michigan Center for Translational Pathology, Ann Arbor, Michigan.