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Oncotarget: Camptothecin targets WRN protein: in clinical breast cancer


Here is a link to a video interview with Dr. Vihelm A. Bohr about this research on the Oncotarget YouTube Channel

Oncotarget published "Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer" which reported that in the cells treated with CPT, the authors observed distinct effects on WRN compared to other human RecQ helicases.

WRN knockdown cells as well as CPT treated cells became senescent and stained positive for senescence-associated β-galactosidase at a higher frequency compared to control cells.

However, the senescent phenotype was attenuated by ectopic expression of WRN suggesting functional implication of WRN degradation in CPT treated cells.

Interestingly, the Oncotarget authors found that the extent of CPT-induced WRN degradation correlates with increasing sensitivity of breast cancer cells to CPT.

The Oncotarget authors found that the extent of CPT-induced WRN degradation correlates with increasing sensitivity of breast cancer cells to CPT

The abundance of WRN decreased in CPT-treated sensitive cells; however, WRN remained relatively stable in CPT-resistant breast cancer cells.

Dr. Vilhelm A. Bohr from The National Institute on Aging, NIH, said, "The RecQ family of helicases contains highly conserved and ubiquitously expressed proteins that unwind DNA in the context of replication, repair, transcription, chromatin remodeling and telomere maintenance."

Increased WRN expression is observed in several cancer cell lines and depletion of WRN induces cell death in these cells.

WS and BS patient cells are hypersensitive to inhibitors of Top1 and DNA interstrand crosslinking agents, and a synergistic increase in chromosomal aberrations is observed in BLM-WRN double knockout cells exposed to these agents.

Figure 7: Kaplan Meier curves showing BCSS with WRN and Top1 expression. a. WRN and Top1 expression in whole cohort. b. and c. combined expression of WRN and Top1 in ER positive and ER negative METABRIC cohorts.

In this study, the authors tested the effects of CPT on the five RecQ helicases in cellular studies and bioinformatically analyzed the association between CPT sensitivity and WRN gene expression.

Further they analyzed the expression profiles of WRN and Top1 in a large cohort of human breast cancers to identify any correlations between gene expression and breast cancer specific survival.

WRN degradation was more extensive in CPT-sensitive breast cancer cells than in CPT-resistant cells.

The Bohr Research Team concluded in their Oncotarget Priority Research Paper, "we provide the first pre-clinical evidence that WRN degradation is a biomarker of CPT sensitivity in breast cancer cells, where it can distinguish CPT- sensitive and resistant breast cancer cells. Therefore, WRN expression and degradation could be used to identify tumors which may be sensitive to CPT and its derivatives. However, a prospective clinical trial of Top1 inhibitor therapy in ER positive breast cancers would be required to confirm our in vitro results. Additionally we show that in human breast cancers, Top1 and/or WRN expression has prognostic and predictive significance. Top1/ WRN expression based stratification could be a promising approach to personalize Top1 inhibitor therapy in breast cancer patients."

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DOI - https://doi.org/10.18632/oncotarget.7906

Full text - https://www.oncotarget.com/article/7906/text/

Correspondence to - Vilhelm A. Bohr - vbohr@nih.gov

Keywords - breast cancer, Werner syndrome, helicase, camptothecin, topoisomerase I

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