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08 2016 Nature communications

Stratification and therapeutic potential of PML in metastatic breast cancer.


Martín-Martín N, Piva M, Urosevic J, Aldaz P, Sutherland JD, Fernández-Ruiz S, Arreal L, Torrano V, Cortazar AR, Planet E, Guiu M, Radosevic-Robin N, Macías I, Salvador F, Domenici G, Rueda OM, Zabala-Letona A, Arruabarrena-Aristorena A, Zúñiga-García P, Caro-Maldonado A, Valcárcel-Jiménez L, Sánchez-Mosquera P, Varela-Rey M, Martínez-Chantar ML, Anguita J, Ibrahim YH, Scaltriti M, Lawrie CH, Aransay AM, Iovanna JL, Baselga J, Caldas C, Barrio R, Serra V, Vivanco Md, Matheu A, Gomis RR, Carracedo A


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.

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