BMI1 Nuclear Location is Critical for RAD51-dependent Response to Replication Stress and Drives Chemoresistance in Breast Cancer Stem Cells

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2022 Feb 3

PMID 35110528

Authors

Violette Azzoni

Julien Wicinski

Manon Macario

Martin Castagne

Pascal Finetti

Katerina Ambrosova

Celia D Rouault

Arnaud Serge

Anne Farina

Emilie Agavnian

Sergiu Coslet

Emmanuelle Josselin

Arnaud Guille

Jose Adelaide

Emmanouil Zacharioudakis

Remy Castellano

Francois Bertucci

Daniel Birnbaum

Raphael Rodriguez

Emmanuelle Charafe-Jauffret

Christophe Ginestier

Affiliations

Soon will be listed here.

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.

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