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Maternal Embryonic Leucine Zipper Kinase (MELK) as a Novel Mediator and Biomarker of Radioresistance in Human Breast Cancer
Clinical cancer research, 2016-12, Vol.22 (23), p.5864-5875
Speers, Corey
Zhao, Shuang G
Kothari, Vishal
Santola, Alyssa
Liu, Meilan
Wilder-Romans, Kari
Evans, Joseph
Batra, Nidhi
Bartelink, Harry
Hayes, Daniel F
Lawrence, Theodore S
Brown, Powel H
Pierce, Lori J
Feng, Felix Y
2016
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
Speers, Corey
Zhao, Shuang G
Kothari, Vishal
Santola, Alyssa
Liu, Meilan
Wilder-Romans, Kari
Evans, Joseph
Batra, Nidhi
Bartelink, Harry
Hayes, Daniel F
Lawrence, Theodore S
Brown, Powel H
Pierce, Lori J
Feng, Felix Y
Titel
Maternal Embryonic Leucine Zipper Kinase (MELK) as a Novel Mediator and Biomarker of Radioresistance in Human Breast Cancer
Ist Teil von
Clinical cancer research, 2016-12, Vol.22 (23), p.5864-5875
Ort / Verlag
United States
Erscheinungsjahr
2016
Quelle
MEDLINE
Beschreibungen/Notizen
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. 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. 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. 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. Clin Cancer Res; 22(23); 5864-75. ©2016 AACR.
Sprache
Englisch
Identifikatoren
ISSN: 1078-0432
eISSN: 1557-3265
DOI: 10.1158/1078-0432.ccr-15-2711
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8820108
Format
–
Schlagworte
Animals
,
Biomarkers, Tumor - metabolism
,
Cell Line, Tumor
,
Cell Proliferation - physiology
,
Disease-Free Survival
,
Female
,
Humans
,
Kaplan-Meier Estimate
,
MCF-7 Cells
,
Mice
,
Neoplasm Recurrence, Local - metabolism
,
Protein Serine-Threonine Kinases - metabolism
,
Radiation Tolerance - physiology
,
Receptor, ErbB-2
,
Triple Negative Breast Neoplasms - metabolism
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