title: CLIC3 controls recycling of late endosomal MT1-MMP and dictates invasion and metastasis in breast cancer.
abstract: Chloride intracellular channel 3 (CLIC3) drives invasiveness of pancreatic and ovarian cancer by acting in concert with Rab25 to regulate the recycling of α5β1 integrin from late endosomes to the plasma membrane. Here, we show that in two estrogen receptor (ER)-negative breast cancer cell lines, CLIC3 has little influence on integrin recycling, but controls trafficking of the pro-invasive matrix metalloproteinase MT1-MMP (also known as MMP14). In MDA-MB-231 cells, MT1-MMP and CLIC3 are localized primarily to late endosomal/lysosomal compartments located above the plane of adhesion and near the nucleus. MT1-MMP is transferred from these late endosomes to sites of cell-matrix adhesion in a CLIC3-dependent fashion. Correspondingly, CLIC3-knockdown opposes MT1-MMP-dependent invasive processes. These include the disruption of the basement membrane as acini formed from MCF10DCIS.com cells acquire invasive characteristics in 3D culture, and the invasion of MDA-MB-231 cells into Matrigel or organotypic plugs of type I collagen. Consistent with this, expression of CLIC3 predicts poor prognosis in ER-negative breast cancer. The identification of MT1-MMP as a cargo of a CLIC3-regulated pathway that drives invasion highlights the importance of late endosomal sorting and trafficking in breast cancer.
authors.affiliation: Beatson Institute for Cancer Research: Garscube Estate, Glasgow G61 1BD, UK Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK iain.macpherson@glasgow.ac.uk j.norman@beatson.gla.ac.uk.
authors.forename: Iain R
authors.initials: IR
authors.lastname: Macpherson
authors.affiliation: Beatson Institute for Cancer Research: Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Rainero
authors.affiliation: Beatson Institute for Cancer Research: Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Mitchell
authors.affiliation: Beatson Institute for Cancer Research: Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Peter V E
authors.initials: PV
authors.lastname: van den Berghe
authors.affiliation: Beatson Institute for Cancer Research: Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Speirs
authors.affiliation: Beatson Institute for Cancer Research: Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Marta A
authors.initials: MA
authors.lastname: Dozynkiewicz
authors.affiliation: Beatson Institute for Cancer Research: Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Suman
authors.initials: S
authors.lastname: Chaudhary
authors.affiliation: Beatson Institute for Cancer Research: Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kalna
authors.affiliation: Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Edwards
authors.affiliation: Beatson Institute for Cancer Research: Garscube Estate, Glasgow G61 1BD, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.affiliation: Beatson Institute for Cancer Research: Garscube Estate, Glasgow G61 1BD, UK iain.macpherson@glasgow.ac.uk j.norman@beatson.gla.ac.uk.
authors.forename: Jim C
authors.initials: JC
authors.lastname: Norman
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D005260:Female; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D021381:Protein Transport
chemical_list: C117019:CLIC3 protein, human; D018118:Chloride Channels; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: Breast cancer; CLIC3; DCIS; ER-negative; Invasion; Late endosome; MMP14; MT1-MMP; Recycling