title: Radiation-induced lung metastasis development is MT1-MMP-dependent in a triple-negative breast cancer mouse model.
abstract: BACKGROUND
  The prognosis of triple-negative breast cancer (TNBC) is still difficult to establish. Some TNBC benefit from radiotherapy (RT) and are cured, while in other patients metastases appear during the first 3 years after treatment. In this study, an animal model of TNBC was used to determine whether the expression of the cell membrane protease MT1-MMP in cancer cells was associated with radiation-stimulated development of lung metastases.
  
  
  METHODS
  Using invasion chambers, irradiated fibroblasts were used as chemoattractants to assess the invasiveness of TNBC D2A1 cell lines showing downregulated expression of MT1-MMP, which were compared with D2A1-wt (wild-type) and D2A1 shMT1-mock (empty vector) cell lines. In a mouse model, a mammary gland was irradiated followed by the implantation of the downregulated MT1-MMP D2A1, D2A1-wt or D2A1 shMT1-mock cell lines. Migration of D2A1 cells in the mammary gland, number of circulating tumour cells and development of lung metastases were assessed.
  
  
  RESULTS
  The reduction of MT1-MMP expression decreased the invasiveness of D2A1 cells and blocked the radiation enhancement of cancer cell invasion. In BALB/c mice, irradiation of the mammary gland has stimulated the invasion of cancer cells, which was associated with a higher number of circulating tumour cells and of lung metastases. These adverse effects of radiation were prevented by downregulating the MT1-MMP.
  
  
  CONCLUSIONS
  This study shows that the MT1-MMP is necessary for the radiation enhancement of lung metastasis development, and that its expression level and/or localisation could be evaluated as a biomarker for predicting the early recurrence observed in some TNBC patients.
authors.affiliation: Centre for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Sherbrooke, Québec, Canada.
authors.forename: Gina
authors.initials: G
authors.lastname: Bouchard
authors.affiliation: Centre for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Sherbrooke, Québec, Canada.
authors.forename: Hélène
authors.initials: H
authors.lastname: Therriault
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Sameh
authors.initials: S
authors.lastname: Geha
authors.affiliation: Centre for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Sherbrooke, Québec, Canada.|Service of Radiation Oncology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bujold
authors.affiliation: Department of Anatomy and Cellular Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Saucier
authors.affiliation: Centre for Research in Radiotherapy, Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Sherbrooke, Québec, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Paquette
mesh_terms: D016475:3T3 Cells; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000473:pathology*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology*
chemical_list: D053511:Matrix Metalloproteinase 14