title: Maternal Embryonic Leucine Zipper Kinase (MELK) as a Novel Mediator and Biomarker of Radioresistance in Human Breast Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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. Clin Cancer Res; 22(23); 5864-75. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. cspeers@umich.edu.
authors.forename: Corey
authors.initials: C
authors.lastname: Speers
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Shuang G
authors.initials: SG
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Vishal
authors.initials: V
authors.lastname: Kothari
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Santola
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Meilan
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kari
authors.initials: K
authors.lastname: Wilder-Romans
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Joseph
authors.initials: J
authors.lastname: Evans
authors.affiliation: Department of Cancer Prevention, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Batra
authors.affiliation: Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Harry
authors.initials: H
authors.lastname: Bartelink
authors.affiliation: Clinical Director, Breast Oncology Program, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.affiliation: Department of Cancer Prevention, MD Anderson Cancer Center, Houston, Texas.
authors.forename: Powel H
authors.initials: PH
authors.lastname: Brown
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Pierce
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.|Michigan Center for Translational Pathology, Ann Arbor, Michigan.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011836:Radiation Tolerance / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C484610:MELK protein, human