title: S100A4 Elevation Empowers Expression of Metastasis Effector Molecules in Human Breast Cancer.
abstract: Many human glandular cancers metastasize along nerve tracts, but the mechanisms involved are generally poorly understood. The calcium-binding protein S100A4 is expressed at elevated levels in human cancers, where it has been linked to increased invasion and metastasis. Here we report genetic studies in a Drosophila model to define S100A4 effector functions that mediate metastatic dissemination of mutant Ras-induced tumors in the developing nervous system. In flies overexpressing mutant RasVal12and S100A4, there was a significant increase in activation of the stress kinase JNK and production of the matrix metalloproteinase MMP1. Genetic or chemical blockades of JNK and MMP1 suppressed metastatic dissemination associated with S100A4 elevation, defining required signaling pathway(s) for S100A4 in this setting. In clinical specimens of human breast cancer, elevated levels of the mammalian paralogs MMP2, MMP9, and MMP13 are associated with a 4- to 9-fold relative decrease in patient survival. In individual tumors, levels of MMP2 and MMP13 correlated more closely with levels of S100A4, whereas MMP9 levels correlated more closely with the S100 family member S100P. Overall, our results suggest the existence of evolutionarily conserved pathways used by S100A4 to promote metastatic dissemination, with potential prognostic and therapeutic implications for metastasis by cancers that preferentially exploit nerve tract migration routes. Cancer Res; 77(3); 780-9. ©2016 AACR.
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Thamir M
authors.initials: TM
authors.lastname: Ismail
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Daimark
authors.initials: D
authors.lastname: Bennett
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Platt-Higgins
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Morteta
authors.initials: M
authors.lastname: Al-Medhity
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Roger
authors.initials: R
authors.lastname: Barraclough
authors.affiliation: Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom. rudland@liverpool.ac.uk.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rudland
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002277:Carcinoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D004330:Drosophila; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D016016:Proportional Hazards Models; D000071999:S100 Calcium-Binding Protein A4 / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000071999:S100 Calcium-Binding Protein A4; C077591:S100A4 protein, human; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D018631:ras Proteins