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

Arnaud Guillé ,Sergiu Coslet ,Manon Macario ,Katerina Ambrosova ,Célia D Rouault ,Anne Farina ,Daniel Birnbaum ,Emmanuelle Charafe-Jauffret ,Emilie Agavnian ,Raphaël Rodriguez ,Martin Castagné ,François Bertucci ,Emmanuelle Josselin ,Pascal Finetti ,Christophe Ginestier ,José Adélaı̈de ,Arnauld Sergé ,Violette Azzoni ,Julien Wicinski ,Rémy Castellano ,Emmanouil Zacharioudakis

doi:10.1038/s41419-022-04538-w

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.

Highlights

Cancer cells are characterized by a loss of control mechanisms for DNA replication, which causes cellular stress named replication stress (RS)
We show that BMI1/RAD51 axis play a pivotal role in the therapeutic resistance of breast cancer stem cells (CSCs) (bCSCs) to DNA-damaging agents and provided evidence that inhibiting RAD51 can chemosensitize bCSCs
Breast CSCs present a limited level of replication stress (RS) To evaluate the RS level in breast CSCs compare with nonbCSCs, we sorted SUM159 cells based on their ALDH enzymatic activity [6, 11] and cell cycle stages (Supplementary Fig. 1)

Summary

Introduction

Cancer cells are characterized by a loss of control mechanisms for DNA replication, which causes cellular stress named replication stress (RS) It results in the generation of inefficient DNA replication, leading to genome instability and genomic alterations [1]. This phenomenon, referred as a hallmark of cancer, is a central driver to tumor initiation and progression [2]. It is of major interest to gain insight into the collaboration between stemness and RS in order to better understand the evolution of cancers’ clonal architecture during tumor progression and propose new approaches to overcome therapeutic failures

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