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  • BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells.

BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells.

Cell death & disease (2022-02-04)
Violette Azzoni, Julien Wicinski, Manon Macario, Martin Castagné, Pascal Finetti, Katerina Ambrosova, Célia D Rouault, Arnaud Sergé, Anne Farina, Emilie Agavnian, Sergiu Coslet, Emmanuelle Josselin, Arnaud Guille, José Adelaide, Emmanouil Zacharioudakis, Rémy Castellano, Francois Bertucci, Daniel Birnbaum, Raphael Rodriguez, Emmanuelle Charafe-Jauffret, Christophe Ginestier
ABSTRACT

Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells' (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
RAD51 Inhibitor B02, ≥98% (HPLC)
Sigma-Aldrich
Monoclonal Anti-Vinculin antibody produced in mouse, clone hVIN-1, ascites fluid
Sigma-Aldrich
Anti-Bmi-1 Antibody, clone F6, Alexa Fluor 488, clone F6, from mouse, ALEXA FLUOR 488
Sigma-Aldrich
5-Aza-2′-deoxycytidine, ≥97%