A transcription-based mechanism for oncogenic \u03b2-catenin-induced lethality in BRCA1/2-deficient cells

Rebecca A Dagg,Andrés Aguilera,Benjamin Wright,Helen Lockstone,Florian J Groelly,Sonia Barroso,Gijs Zonderland,Thanos D Halazonetis,Madalena Tarsounas,Emilia Puig Lombardi,Eliana M C Tacconi,Giacomo G Rossetti

doi:10.1038/s41467-021-25215-0

Abstract

BRCA1 or BRCA2 germline mutations predispose to breast, ovarian and other cancers. High-throughput sequencing of tumour genomes revealed that oncogene amplification and BRCA1/2 mutations are mutually exclusive in cancer, however the molecular mechanism underlying this incompatibility remains unknown. Here, we report that activation of β-catenin, an oncogene of the WNT signalling pathway, inhibits proliferation of BRCA1/2-deficient cells. RNA-seq analyses revealed β-catenin-induced discrete transcriptome alterations in BRCA2-deficient cells, including suppression of CDKN1A gene encoding the CDK inhibitor p21. This accelerates G1/S transition, triggering illegitimate origin firing and DNA damage. In addition, β-catenin activation accelerates replication fork progression in BRCA2-deficient cells, which is critically dependent on p21 downregulation. Importantly, we find that upregulated p21 expression is essential for the survival of BRCA2-deficient cells and tumours. Thus, our work demonstrates that β-catenin toxicity in cancer cells with compromised BRCA1/2 function is driven by transcriptional alterations that cause aberrant replication and inflict DNA damage.

Highlights

BRCA1 or BRCA2 germline mutations predispose to breast, ovarian and other cancers
Co-occurrence of CCND1 and CCNE1 gene amplification with BRCA1/2 gene mutations was not found in tumours[18,19,20], these studies have not indicated whether these amplification events correspond to increased expression of the respective genes
Re-analysed The Cancer Genome Atlas (TCGA) data[18] for amplification of known oncogenes in breast (n = 472) and ovarian (n = 311) cancer patient cohorts, and we investigated whether it correlates with increased mRNA expression

Summary

Introduction

BRCA1 or BRCA2 germline mutations predispose to breast, ovarian and other cancers. Highthroughput sequencing of tumour genomes revealed that oncogene amplification and BRCA1/ 2 mutations are mutually exclusive in cancer, the molecular mechanism underlying this incompatibility remains unknown. RNA-seq analyses revealed β-catenin-induced discrete transcriptome alterations in BRCA2deficient cells, including suppression of CDKN1A gene encoding the CDK inhibitor p21 This accelerates G1/S transition, triggering illegitimate origin firing and DNA damage. BRCA1 and BRCA2 proteins have physiological roles in maintaining genome integrity, by promoting DNA double-stand break (DSB) repair via homologous recombination and facilitating DNA replication The latter relies on the ability of BRCA1/2 to re-start, stabilise and protect stalled replication forks against nucleolytic degradation[2]. In cells lacking BRCA1 or BRCA2 replication failure leads to spontaneous DSBs and chromosomal rearrangements This intrinsic genomic instability represents a hallmark of BRCA-deficient cells and tumours and underlies their sensitivity to chemotherapy that inflicts further DNA damage[5,9]

Methods

Results

Conclusion