A transcription-based mechanism for oncogenic β-catenin-induced lethality in BRCA1/2-deficient cells
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. ; We are grateful to members of M.T. laboratory for critical reading of the manuscript and valuable feedback. Andrés Aguilera's laboratory is funded by the European Research Council (grant ERC2014 AdG669898 TARLOOP). The work in Thanos Halazonetis' laboratory was supported by grants from the Swiss National Science Foundation (182487) and the European Commission (ERC project REPLISTRESS). Research in Madalena Tarsounas' laboratory is supported by Cancer Research UK and University of Oxford. This project has received funding from long-term EMBO non-stipendiary fellowship (ALTF 1044-2019), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 722729 and grant agreement No. 886045. M.T. was the recipient of a Mayent-Rothschild-Institute Curie Award.