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.
Highlights
Patients who develop triple-negative breast cancer (TNBC), i.e., those breast cancers that lack amplification of the Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.ERBB2 gene as well as expression of both the oestrogen and progesterone receptors, tend to have a relatively poor prognosis and represent a significant area of unmet clinical need, where novel therapeutic approaches are acutely needed
To identify highly robust synthetic lethal effects associated with Rb defects in TNBC, we classified a molecularly diverse panel of TNBC tumour cell lines (TCLs) according to Rb status and used this Rb classification to interrogate publically available genetic screen data using a data analysis pipeline that identified highly penetrant synthetic lethal effects
Using average intensity-based absolute protein abundance data for Rb from mass spectrometry profiling [24] (Supplementary Data 1), we found that TNBC TCLs classified by western blotting as being Rb-defective exhibited no Rb peptides (MDAMB468, MDAMB436, HCC1937, DU4475, BT549) when compared to those TCLs we had classified as Rb-proficient (Fig. 1c, p = 0.0002), giving us some confidence in our classification
Summary
Some targeted approaches have been proposed for molecularly defined subsets of TNBC patients, for most, classical chemotherapy regimens still represent the mainstay of treatment, making the requirement to identify novel targets in this disease critical. One approach to this problem has been to define the molecular composition of TNBCs and to use this information to help identify therapeutic vulnerabilities that might operate in the disease. A somewhat reductionist model of Rb’s role in tumour suppression suggests that loss of Rb’s E2F repressive function allows premature transition of cells through the G1 cell cycle checkpoint; it seems likely that loss of Rb function in breast cancer influences additional processes that contribute to the development of the disease, including the differentiation of stem and progenitor cells and the transition of cells from an epithelial to a mesenchymal phenotype [3]
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