Identification of highly penetrant Rb-related synthetic lethal interactions in triple negative breast cancer.
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ICR Authors
Authors
Brough, R
Gulati, A
Haider, S
Kumar, R
Campbell, J
Knudsen, E
Pettitt, SJ
Ryan, CJ
Lord, CJ
Gulati, A
Haider, S
Kumar, R
Campbell, J
Knudsen, E
Pettitt, SJ
Ryan, CJ
Lord, CJ
Document Type
Journal Article
Date
2018-10-25
Date Accepted
2018-05-21
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.
Citation
Oncogene, 2018, 37 (43), pp. 5701 - 5718
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
0950-9232
eISSN
1476-5594
Collections
Research Team
Gene Function