Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer

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Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer. / Englund, E; Bartoschek, M; Reitsma, B; Jacobsson, L; Escudero-Esparza, A; Orimo, Akira; Leandersson, K; Hagerling, C; Aspberg, A; Storm, P; Okroj, M; Mulder, H; Jirström, K; Pietras, K; Blom, A M.

In: Oncogene, Vol. 35, No. 43, 2016, p. 5585-5596.

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Englund E, Bartoschek M, Reitsma B, Jacobsson L, Escudero-Esparza A, Orimo A et al. Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer. Oncogene. 2016;35(43):5585-5596. https://doi.org/10.1038/onc.2016.98

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Englund, E ; Bartoschek, M ; Reitsma, B ; Jacobsson, L ; Escudero-Esparza, A ; Orimo, Akira ; Leandersson, K ; Hagerling, C ; Aspberg, A ; Storm, P ; Okroj, M ; Mulder, H ; Jirström, K ; Pietras, K ; Blom, A M. / Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer. In: Oncogene. 2016 ; Vol. 35, No. 43. pp. 5585-5596.

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TY - JOUR

T1 - Cartilage oligomeric matrix protein contributes to the development and metastasis of breast cancer

AU - Englund, E

AU - Bartoschek, M

AU - Reitsma, B

AU - Jacobsson, L

AU - Escudero-Esparza, A

AU - Orimo, Akira

AU - Leandersson, K

AU - Hagerling, C

AU - Aspberg, A

AU - Storm, P

AU - Okroj, M

AU - Mulder, H

AU - Jirström, K

AU - Pietras, K

AU - Blom, A M

PY - 2016

Y1 - 2016

N2 - 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-Prkdc(scid)/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.

AB - 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-Prkdc(scid)/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.

KW - Animals

KW - Apoptosis

KW - Biomarkers, Tumor

KW - Breast Neoplasms

KW - Cartilage Oligomeric Matrix Protein

KW - Cell Adhesion

KW - Cell Line

KW - Cell Membrane

KW - Cell Movement

KW - Cell Transformation, Neoplastic

KW - Disease Models, Animal

KW - Endoplasmic Reticulum

KW - Endoplasmic Reticulum Stress

KW - Female

KW - Gene Expression

KW - Gene Expression Profiling

KW - Heterografts

KW - Humans

KW - Immunohistochemistry

KW - Matrix Metalloproteinase 9

KW - Mice, SCID

KW - Neoplasm Metastasis

KW - Oxidative Phosphorylation

KW - Prognosis

KW - Proportional Hazards Models

KW - Recurrence

KW - Journal Article

U2 - 10.1038/onc.2016.98

DO - 10.1038/onc.2016.98

M3 - Article

VL - 35

SP - 5585

EP - 5596

JO - Oncogene

JF - Oncogene

SN - 1476-5594

IS - 43

ER -