title: LMTK3 expression in breast cancer: association with tumor phenotype and clinical outcome.
abstract: Interactions between kinases and the estrogen receptor α (ERα) are thought to be a critical signaling pathway in the majority of human breast cancers. We have recently identified a previously uncharacterized molecule, lemur tyrosine kinase-3 (LMTK3) as a prognostic and predictive oncogenic ERα regulator with a central role in endocrine resistance. Unusually this protein has undergone Darwinian positive selection between Chimpanzees and humans suggesting it may contribute to human susceptibility to ERα-positive tumors. Using over 600 European primary breast cancer cases, we wished to establish tumor characteristics associated with both cytoplasmic and nuclear LMTK3 expression, and then externally validate our observed European clinical outcomes with samples from Asian individuals receiving chemotherapy. Both nuclear and cytoplasmic expression correlated with tumor grade (P < 0.001) and in the Asian cohort, independent blinded analyses demonstrated that high basal LMTK3 expression was associated with advanced stage of primary breast cancers as well as decreased overall (P = 0.03) and disease-free survival (P = 0.006). In summary, higher LMTK3 expression is associated with more aggressive cancers. These data support our previous findings and suggest LMTK3 expression may be a reliable new biomarker in breast cancer.
authors.affiliation: Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK. j.stebbing@imperial.ac.uk
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Filipovic
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.forename: Tanya Rapoz
authors.initials: TR
authors.lastname: D'Silva
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.forename: Soo-Chin
authors.initials: SC
authors.lastname: Lee
authors.forename: Georgios
authors.initials: G
authors.lastname: Giamas
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000208:ethnology / Q000401:mortality / Q000473:pathology; D002467:Cell Nucleus / Q000201:enzymology; D016009:Chi-Square Distribution; D003593:Cytoplasm / Q000201:enzymology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008131:London / Q000453:epidemiology; D008565:Membrane Proteins / Q000032:analysis*; D008875:Middle Aged; D015999:Multivariate Analysis; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010641:Phenotype; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000032:analysis*; D018570:Risk Assessment; D012307:Risk Factors; D012846:Singapore / Q000453:epidemiology; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation; D044465:White People
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C560359:LMTK3 protein, human; D017346:Protein Serine-Threonine Kinases