2026-09-21T10:19:44Zhttps://api.repository.cam.ac.uk/server/oai/request

oai:www.repository.cam.ac.uk:1810/3931172026-02-27T01:41:02Zcom_1810_245118com_1810_34581col_1810_245119

Identification of therapeutic targets and dependencies in ZNF703-amplified breast cancer https://doi.org/10.17863/CAM.123573 Lui, Allan 0000000176243437 Brenton, James Caldas, Carlos Focal amplifications of the chromosome 8p11.23, likely precipitated by oestrogen-induced chromosomal instability, are recurrent in 15% of breast cancer, defines the IntClust6 subtype, and portends poor prognosis with high risk of late relapse and chemotherapy resistance. ZNF703 is the most frequently amplified gene and the putative driver oncogene within this locus, though mechanisms are poorly understood. To identify therapeutic vulnerabilities for ZNF703-amplified breast cancers, wholegenome CRISPR-Cas9 screens were performed in isogenic cell lines with modulated ZNF703 expression alongside ZNF703-amplified cells. Here we report that ZNF703 amplification is synthetic lethal with loss of OTUD5, a regulator of DNA double strand break repair and interferon signalling. Furthermore, ZNF703 overexpression favours error-free repair of CRISPR-Cas9-induced double strand breaks and confers increased dependency on homologous recombination. Interactomic and transcriptomic profiling suggests ZNF703 binds to transcriptional repressors and interferon-related transcription factors, resulting in downregulation of interferon response. Notably, underexpression of interferon response genes is associated with dependency on OTUD5 and BRCA1. Together, these findings propose that ZNF703 facilitates cell growth under chromosomal instability, and antagonism of this function by OTUD5 loss represents a promising therapeutic strategy. University of Cambridge 2024-10-31 Thesis Doctoral Doctor of Philosophy (PhD) eng Croucher Cambridge International Scholarship https://www.repository.cam.ac.uk/handle/1810/393117 embargo 2031-11-28 https://www.repository.cam.ac.uk/bitstreams/085fce2e-5b52-4913-be13-42106a60e450/download ec416636196b171160242bcf9f4c2a2a https://www.repository.cam.ac.uk/bitstreams/0b2007e9-673d-4c8c-aa36-94b17998a642/download 87eda9de84448d1f82354d60eee3eb5f http://purl.org/NET/rdflicense/allrightsreserved Cancer