title: Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer.
abstract: Cartilage oligomeric matrix protein (COMP) is a soluble pentameric protein expressed in cartilage and involved in collagen organization. Tissue microarrays derived from two cohorts of patients with breast cancer (n=122 and n=498) were immunostained, revealing varying expression of COMP, both in the tumor cells and surrounding stroma. High levels of COMP in tumor cells correlated, independently of other variables, with poor survival and decreased recurrence-free survival. Breast cancer cells, MDA-MB-231, stably expressing COMP were injected into the mammary fat pad of SCID (CB-17/Icr-Prkdcscid/Rj) mice. Tumors expressing COMP were significantly larger and were more prone to metastasize as compared with control, mock-transfected, tumors. In vitro experiments confirmed that COMP-expressing cells had a more invasive phenotype, which could in part be attributed to an upregulation of matrix metalloprotease-9. Furthermore, microarray analyses of gene expression in tumors formed in vivo showed that COMP expression induced higher expression of genes protecting against endoplasmic reticulum stress. This observation was confirmed in vitro as COMP-expressing cells showed better survival as well as a higher rate of protein synthesis when treated with brefeldin A, compared with control cells. Further, COMP-expressing cells appeared to undergo a metabolic switch, that is, a Warburg effect. Thus, in vitro measurement of cell respiration indicated decreased mitochondrial metabolism. In conclusion, COMP is a novel biomarker in breast cancer, which contributes to the severity of the disease by metabolic switching and increasing invasiveness and tumor cell viability, leading to reduced survival in animal models and human patients.
authors.affiliation: Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Englund
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Bartoschek
authors.affiliation: Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Reitsma
authors.affiliation: Department of Clinical Sciences Malmö, Unit of Molecular Metabolism, Lund University, Malmö, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Jacobsson
authors.affiliation: Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Escudero-Esparza
authors.affiliation: Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Orimo
authors.affiliation: Department of Laboratory Medicine, Center for Molecular Pathology, Lund University, Malmö, Sweden.
authors.forename: K
authors.identifier: 0000-0001-8254-3137
authors.initials: K
authors.lastname: Leandersson
authors.affiliation: Department of Laboratory Medicine, Center for Molecular Pathology, Lund University, Malmö, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Hagerling
authors.affiliation: Division of Rheumatology and Molecular Skeletal Biology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Aspberg
authors.affiliation: Division of Diabetes and Endocrinology, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Storm
authors.affiliation: Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden.|Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology UG-MUG, Medical University of Gdańsk, Gdańsk, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Okroj
authors.affiliation: Department of Clinical Sciences Malmö, Unit of Molecular Metabolism, Lund University, Malmö, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Mulder
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Jirström
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Pietras
authors.affiliation: Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, Malmö, Sweden.
authors.forename: A M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D064236:Cartilage Oligomeric Matrix Protein / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D010085:Oxidative Phosphorylation; D011379:Prognosis; D016016:Proportional Hazards Models; D012008:Recurrence
chemical_list: D014408:Biomarkers, Tumor; D064236:Cartilage Oligomeric Matrix Protein; D020780:Matrix Metalloproteinase 9