Identification of highly penetrant Rb-related synthetic lethal interactions in triple negative breast cancer.
MetadataShow full item record
Although defects in the RB1 tumour suppressor are one of the more common driver alterations found in triple-negative breast cancer (TNBC), therapeutic approaches that exploit this have not been identified. By integrating molecular profiling data with data from multiple genetic perturbation screens, we identified candidate synthetic lethal (SL) interactions associated with RB1 defects in TNBC. We refined this analysis by identifying the highly penetrant effects, reasoning that these would be more robust in the face of molecular heterogeneity and would represent more promising therapeutic targets. A significant proportion of the highly penetrant RB1 SL effects involved proteins closely associated with RB1 function, suggesting that this might be a defining characteristic. These included nuclear pore complex components associated with the MAD2 spindle checkpoint protein, the kinase and bromodomain containing transcription factor TAF1, and multiple components of the SCF SKP Cullin F box containing complex. Small-molecule inhibition of SCF SKP elicited an increase in p27 Kip levels, providing a mechanistic rationale for RB1 SL. Transcript expression of SKP2, a SCF SKP component, was elevated in RB1-defective TNBCs, suggesting that in these tumours, SKP2 activity might buffer the effects of RB1 dysfunction.
Cell Line, Tumor
S-Phase Kinase-Associated Proteins
TATA-Binding Protein Associated Factors
Transcription Factor TFIID
Gene Expression Regulation, Neoplastic
Retinoblastoma Binding Proteins
Triple Negative Breast Neoplasms
License start date
Oncogene, 2018, 37 (43), pp. 5701 - 5718
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0
Showing items related by title, author, creator and subject.
Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment. Xiong, S; Lorenzen, K; Couzens, AL; Templeton, CM; Rajendran, D; et al. (2018-08)The human NDR family kinases control diverse aspects of cell growth, and are regulated through phosphorylation and association with scaffolds such as MOB1. Here, we report the crystal structure of the human NDR1 kinase ...
Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint. Bigot, N; Day, M; Baldock, RA; Watts, FZ; Oliver, AW; et al. (2019-05-28)Coordination of the cellular response to DNA damage is organised by multi-domain 'scaffold' proteins, including 53BP1 and TOPBP1, which recognise post-translational modifications such as phosphorylation, methylation and ...
Broderick, R; Nieminuszczy, J; Blackford, AN; Winczura, A; Niedzwiedz, W (2015-03-12)During mitosis, sister chromatids must be faithfully segregated to ensure that daughter cells receive one copy of each chromosome. However, following replication they often remain entangled. Topoisomerase IIα (TOP2A) has ...