title: Stratification and therapeutic potential of PML in metastatic breast cancer.
abstract: Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification.
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Martín-Martín
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Marco
authors.initials: M
authors.lastname: Piva
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine (IRB-Barcelona), 08028 Barcelona, Spain.
authors.forename: Jelena
authors.initials: J
authors.lastname: Urosevic
authors.affiliation: Oncology Area, Biodonostia Institute, 20014 San Sebastian, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Aldaz
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: James D
authors.identifier: 0000-0003-3229-793X
authors.initials: JD
authors.lastname: Sutherland
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fernández-Ruiz
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Leire
authors.initials: L
authors.lastname: Arreal
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Torrano
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Ana R
authors.initials: AR
authors.lastname: Cortazar
authors.affiliation: Biostatistics and Bioinformatics Unit, Institute for Research in Biomedicine (IRB-Barcelona), 08028 Barcelona, Spain.|School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Evarist
authors.initials: E
authors.lastname: Planet
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine (IRB-Barcelona), 08028 Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Guiu
authors.affiliation: ERTICa Research Group, University of Auvergne EA4677, Clermont-Ferrand, France.|Biodiagnostics Laboratory OncoGenAuvergne, Pathology Unit, Jean Perrin Comprehensive Cancer Center, 63000 Clermont-Ferrand, France.
authors.forename: Nina
authors.initials: N
authors.lastname: Radosevic-Robin
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM UMR 1068, CNRS UMR 7258, Aix-Marseille University and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 13288 Marseille, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Garcia
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Iratxe
authors.initials: I
authors.lastname: Macías
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine (IRB-Barcelona), 08028 Barcelona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Salvador
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Domenici
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Zabala-Letona
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Arruabarrena-Aristorena
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Zúñiga-García
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Caro-Maldonado
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Lorea
authors.initials: L
authors.lastname: Valcárcel-Jiménez
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Mosquera
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd).
authors.forename: Marta
authors.initials: M
authors.lastname: Varela-Rey
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd).
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.|IKERBASQUE, Basque foundation for science, 48013 Bilbao, Spain.
authors.forename: Juan
authors.identifier: 0000-0003-2061-7182
authors.initials: J
authors.lastname: Anguita
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron University Hospital, 08035 Barcelona, Spain.|Weill Cornell Medicine, New York 10021, USA.
authors.forename: Yasir H
authors.initials: YH
authors.lastname: Ibrahim
authors.affiliation: Human Oncology and Pathogenesis Program, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 10065 New York, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.affiliation: Oncology Area, Biodonostia Institute, 20014 San Sebastian, Spain.|IKERBASQUE, Basque foundation for science, 48013 Bilbao, Spain.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lawrie
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd).
authors.forename: Ana M
authors.initials: AM
authors.lastname: Aransay
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM UMR 1068, CNRS UMR 7258, Aix-Marseille University and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 13288 Marseille, France.
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
authors.affiliation: Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 10065 New York, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Rosa
authors.identifier: 0000-0002-9663-0669
authors.initials: R
authors.lastname: Barrio
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron University Hospital, 08035 Barcelona, Spain.
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.
authors.forename: Maria dM
authors.initials: Md
authors.lastname: Vivanco
authors.affiliation: Oncology Area, Biodonostia Institute, 20014 San Sebastian, Spain.|IKERBASQUE, Basque foundation for science, 48013 Bilbao, Spain.
authors.forename: Ander
authors.initials: A
authors.lastname: Matheu
authors.affiliation: Oncology Programme, Institute for Research in Biomedicine (IRB-Barcelona), 08028 Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.
authors.forename: Roger R
authors.identifier: 0000-0001-6473-2858
authors.initials: RR
authors.lastname: Gomis
authors.affiliation: CIC bioGUNE, Bizkaia Technology Park, Bulding 801a, 48160 Derio, Spain.|IKERBASQUE, Basque foundation for science, 48013 Bilbao, Spain.|Biochemistry and Molecular Biology Department, University of the Basque Country (UPV/EHU), 48949 Leioa, Spain.
authors.forename: Arkaitz
authors.identifier: 0000-0001-5957-1260
authors.initials: A
authors.lastname: Carracedo
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000556:secondary* / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D010087:Oxides / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D000071156:Promyelocytic Leukemia Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D001152:Arsenicals; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C070576:PML protein, human; D000077237:Arsenic Trioxide