title: RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation.
abstract: In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. We show that RARRES3 downregulation engages metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributes to lung metastasis. Our results establish RARRES3 downregulation as a potential biomarker to identify patients at high risk of lung metastasis who might benefit from a differentiation treatment in the adjuvant programme.
authors.affiliation: Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Morales
authors.affiliation: Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Arenas
authors.affiliation: Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Jelena
authors.initials: J
authors.lastname: Urosevic
authors.affiliation: Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Guiu
authors.affiliation: Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Fernández
authors.affiliation: Biostatistics and Bioinformatics Unit, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Evarist
authors.initials: E
authors.lastname: Planet
authors.affiliation: Joint BSC-IRB Research Programme in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Robert Bryn
authors.initials: RB
authors.lastname: Fenwick
authors.affiliation: CIC bioGUNE Bizkaia Tecnology park, Derio, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fernández-Ruiz
authors.affiliation: Joint BSC-IRB Research Programme in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Salvatella
authors.affiliation: Departament de Bioquímica i de Biologia Molecular, Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Reverter
authors.affiliation: CIC bioGUNE Bizkaia Tecnology park, Derio, Spain Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), Bilbao, Spain Ikerbasque Basque Foundation for Science, Bilbao, Spain.
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Howard Hughes Medical Institute, Chevy Chase, MD, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Massagué
authors.affiliation: Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain roger.gomis@irbbarcelona.org.
authors.forename: Roger R
authors.initials: RR
authors.lastname: Gomis
mesh_terms: D000818:Animals; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*
chemical_list: C437968:PLAAT4 protein, human; D018168:Receptors, Retinoic Acid
keywords: breast cancer; lung metastasis; metastasis suppressor