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Stratification and therapeutic potential of PML in metastatic breast cancer

2016; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/ncomms12595

2041-1723

Natalia Martín-Martín, Marco Piva, Jelena Urosevic, Paula Aldaz, James D. Sutherland, Sonia Fernández‐Ruiz, Leire Arreal, Verónica Torrano, Ana R. Cortázar, Evarist Planet, Marc Guiu, Nina Radosevic‐Robin, Stéphane 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, María Luz Martínez‐Chantar, Juan Anguíta, Yasir H. Ibrahim, Maurizio Scaltriti, Charles H. Lawrie, Ana M. Aransay, Juan Iovanna, José Baselga, Carlos Caldas, Rosa Barrio, Violeta Serra, María dM Vivanco, Ander Matheu, Roger R. Gomis, Arkaitz Carracedo,

Ubiquitin and proteasome pathways

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.