Identification of highly penetrant Rb-related synthetic lethal interactions in triple negative breast cancer
Open Access
- 18 June 2018
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 37 (43), 5701-5718
- https://doi.org/10.1038/s41388-018-0368-z
Abstract
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 SCFSKP Cullin F box containing complex. Small-molecule inhibition of SCFSKP elicited an increase in p27Kip levels, providing a mechanistic rationale for RB1 SL. Transcript expression of SKP2, a SCFSKP component, was elevated in RB1-defective TNBCs, suggesting that in these tumours, SKP2 activity might buffer the effects of RB1 dysfunction.This publication has 68 references indexed in Scilit:
- Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi ScreeningCell, 2017
- RB loss contributes to aggressive tumor phenotypes in MYC-driven triple negative breast cancerCell Cycle, 2015
- Nuclear Pores Protect Genome Integrity by Assembling a Premitotic and Mad1-Dependent Anaphase InhibitorCell, 2014
- Specific Small Molecule Inhibitors of Skp2-Mediated p27 DegradationCell Chemical Biology, 2012
- Essential Gene Profiles in Breast, Pancreatic, and Ovarian Cancer CellsCancer Discovery, 2012
- CpG island hypermethylation ofBRCA1and loss of pRb as co-occurring events in basal/triple-negative breast cancerEpigenetics, 2011
- The Nup107-160 Nucleoporin Complex Is Required for Correct Bipolar Spindle AssemblyMolecular Biology of the Cell, 2006
- A Rae1-Containing Ribonucleoprotein Complex Is Required for Mitotic Spindle AssemblyCell, 2005
- RB protein expression in human endometrial carcinomas — An immunohistochemical studyPathology - Research and Practice, 2000
- The retinoblastoma-susceptibility gene product binds directly to the human TATA-binding protein-associated factor TAFII250.Proceedings of the National Academy of Sciences of the United States of America, 1995