Stratification and therapeutic potential of PML in metastatic breast cancer

Natalia Martín-Martín, Marco Piva, Jelena Urosevic, Paula Aldaz, James D. Sutherland, Sonia Fernández-Ruiz, Leire Arreal, Verónica Torrano, Ana R. Cortazar, Evarist Planet, Marc Guiu, Nina Radosevic-Robin, Stephane Garcia, Iratxe Macías, Fernando Salvador, Giacomo Domenici, Oscar M. Rueda, Amaia Zabala-Letona, Amaia Arruabarrena-Aristorena, Patricia Zúñiga-García, Alfredo Caro-Maldonado, Lorea Valcárcel-Jiménez, Pilar Sánchez-Mosquera, Marta Varela-Rey, Maria Luz Martínez-Chantar, Juan Anguita, Yasir H. Ibrahim, Maurizio Scaltriti, Charles H. Lawrie, Ana M. Aransay, Juan L. Iovanna, Jose Baselga, Carlos Caldas, Rosa Barrio, Violeta Serra, Maria dM Vivanco, Ander Matheu, Roger R. Gomis and Arkaitz Carracedo ()
Additional contact information
Natalia Martín-Martín: CIC bioGUNE, Bizkaia Technology Park
Marco Piva: CIC bioGUNE, Bizkaia Technology Park
Jelena Urosevic: Oncology Programme, Institute for Research in Biomedicine (IRB-Barcelona)
Paula Aldaz: Oncology Area, Biodonostia Institute
James D. Sutherland: CIC bioGUNE, Bizkaia Technology Park
Sonia Fernández-Ruiz: CIC bioGUNE, Bizkaia Technology Park
Leire Arreal: CIC bioGUNE, Bizkaia Technology Park
Verónica Torrano: CIC bioGUNE, Bizkaia Technology Park
Ana R. Cortazar: CIC bioGUNE, Bizkaia Technology Park
Evarist Planet: Biostatistics and Bioinformatics Unit, Institute for Research in Biomedicine (IRB-Barcelona)
Marc Guiu: Oncology Programme, Institute for Research in Biomedicine (IRB-Barcelona)
Nina Radosevic-Robin: ERTICa Research Group, University of Auvergne EA4677
Stephane Garcia: 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
Iratxe Macías: CIC bioGUNE, Bizkaia Technology Park
Fernando Salvador: Oncology Programme, Institute for Research in Biomedicine (IRB-Barcelona)
Giacomo Domenici: CIC bioGUNE, Bizkaia Technology Park
Oscar M. Rueda: Cancer Research UK Cambridge Institute, University of Cambridge
Amaia Zabala-Letona: CIC bioGUNE, Bizkaia Technology Park
Amaia Arruabarrena-Aristorena: CIC bioGUNE, Bizkaia Technology Park
Patricia Zúñiga-García: CIC bioGUNE, Bizkaia Technology Park
Alfredo Caro-Maldonado: CIC bioGUNE, Bizkaia Technology Park
Lorea Valcárcel-Jiménez: CIC bioGUNE, Bizkaia Technology Park
Pilar Sánchez-Mosquera: CIC bioGUNE, Bizkaia Technology Park
Marta Varela-Rey: CIC bioGUNE, Bizkaia Technology Park
Maria Luz Martínez-Chantar: CIC bioGUNE, Bizkaia Technology Park
Juan Anguita: CIC bioGUNE, Bizkaia Technology Park
Yasir H. Ibrahim: Experimental Therapeutics Group, Vall d'Hebron University Hospital
Maurizio Scaltriti: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center
Charles H. Lawrie: Oncology Area, Biodonostia Institute
Ana M. Aransay: CIC bioGUNE, Bizkaia Technology Park
Juan L. Iovanna: 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
Jose Baselga: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center
Carlos Caldas: Cancer Research UK Cambridge Institute, University of Cambridge
Rosa Barrio: CIC bioGUNE, Bizkaia Technology Park
Violeta Serra: Experimental Therapeutics Group, Vall d'Hebron University Hospital
Maria dM Vivanco: CIC bioGUNE, Bizkaia Technology Park
Ander Matheu: Oncology Area, Biodonostia Institute
Roger R. Gomis: Oncology Programme, Institute for Research in Biomedicine (IRB-Barcelona)
Arkaitz Carracedo: CIC bioGUNE, Bizkaia Technology Park

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12595

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