title: Inflammatory peroxidases promote breast cancer progression in mice via regulation of the tumour microenvironment.
abstract: Myeloperoxidase (MPO) and eosinophil peroxidase (EPO) are heme-containing enzymes, well known for their antimicrobial activity, are released in high quantities by infiltrating immune cells in breast cancer. However, the functional importance of their presence within the tumour microenvironment is unclear. We have recently described a new role for peroxidases as key regulators of fibroblast and endothelial cell functionality. In the present study, we investigate for the first time, the ability of peroxidases to promote breast cancer development and progression. Using the 4T1 syngeneic murine orthotopic breast cancer model, we examined whether increased levels of peroxidases in developing mammary tumours influences primary tumour growth and metastasis. We showed that MPO and EPO stimulation increased mammary tumour growth and enhanced lung metastases, effects that were associated with reduced tumour necrosis, increased collagen deposition and neo-vascularisation within the primary tumour. In vitro, peroxidase treatment, robustly stimulated human mammary fibroblast migration and collagen type I and type VI secretion. Mechanistically, peroxidases induced the transcription of pro-tumorigenic and metastatic MMP1, MMP3 and COX-2 genes. Taken together, these findings identify peroxidases as key contributors to cancer progression by augmenting pro-tumorigenic collagen production and angiogenesis. Importantly, this identifies inflammatory peroxidases as therapeutic targets in breast cancer therapy.
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Panagopoulos
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Damien A
authors.initials: DA
authors.lastname: Leach
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Irene
authors.initials: I
authors.lastname: Zinonos
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ponomarev
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Licari
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Liapis
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Wendy V
authors.initials: WV
authors.lastname: Ingman
authors.affiliation: Australian Craniofacial Unit, Women's and Children's Health Network, Adelaide, SA, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Anderson
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Mark O
authors.initials: MO
authors.lastname: DeNichilo
authors.affiliation: Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
mesh_terms: D000818:Animals; D001940:Breast / Q000098:blood supply; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D024042:Collagen Type I / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D018450:Disease Progression; D047209:Eosinophil Peroxidase / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism*; D061251:Primary Cell Culture; D011994:Recombinant Proteins / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D024042:Collagen Type I; D024141:Collagen Type IV; D011994:Recombinant Proteins; D047209:Eosinophil Peroxidase; D009195:Peroxidase; D051546:Cyclooxygenase 2; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1