Towards resolution of the intron retention paradox in breast cancer

Breast Cancer Research

Research

Jane E. Visvader¹  Michael J. G. Milevskiy¹  Ulf Schmitz²  Veronika Petrova³  Jaynish S. Shah⁴  Justin J. L. Wong⁵  Amy Y. M. Au⁶  John E. J. Rasko⁷ 

[1] ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, 3052, Parkville, VIC, Australia;Department of Medical Biology, The University of Melbourne, 3010, Parkville, VIC, Australia;Computational BioMedicine Laboratory Centenary Institute, The University of Sydney, Camperdown, Australia;Department of Molecular and Cell Biology, College of Public Health, Medical and Veterinary Sciences, James Cook University, 1 James Cook Drive, 4811, Townsville, QLD, Australia;Centre for Tropical Bioinformatics and Molecular Biology, Australian Institute of Tropical Health and Medicine, James Cook University, 4878, Cairns, Australia;Computational BioMedicine Laboratory Centenary Institute, The University of Sydney, Camperdown, Australia;Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Locked Bag No. 6, 2042, Newtown, NSW, Australia;Computational BioMedicine Laboratory Centenary Institute, The University of Sydney, Camperdown, Australia;Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Locked Bag No. 6, 2042, Newtown, NSW, Australia;Australian Centre for Blood Diseases, Central Clinical School, Monash University and Alfred Health, Melbourne, VIC, Australia;Epigenetics and RNA Biology Program Centenary Institute, The University of Sydney, 2050, Camperdown, Australia;Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia;Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Locked Bag No. 6, 2042, Newtown, NSW, Australia;Gene and Stem Cell Therapy Program Centenary Institute, The University of Sydney, Locked Bag No. 6, 2042, Newtown, NSW, Australia;Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia;Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, Australia;

关键词: Alternative splicing;    Patient stratification;    Luminal B breast cancer;    Adipocytes;    Cancer transcriptomics;   

DOI  :  10.1186/s13058-022-01593-1

 received in 2022-07-10, accepted in 2022-12-12,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundAfter many years of neglect in the field of alternative splicing, the importance of intron retention (IR) in cancer has come into focus following landmark discoveries of aberrant IR patterns in cancer. Many solid and liquid tumours are associated with drastic increases in IR, and such patterns have been pursued as both biomarkers and therapeutic targets. Paradoxically, breast cancer (BrCa) is the only tumour type in which IR is reduced compared to adjacent normal breast tissue.MethodsIn this study, we have conducted a pan-cancer analysis of IR with emphasis on BrCa and its subtypes. We explored mechanisms that could cause aberrant and pathological IR and clarified why normal breast tissue has unusually high IR.ResultsStrikingly, we found that aberrantly decreasing IR in BrCa can be largely attributed to normal breast tissue having the highest occurrence of IR events compared to other healthy tissues. Our analyses suggest that low numbers of IR events in breast tumours are associated with poor prognosis, particularly in the luminal B subtype. Interestingly, we found that IR frequencies negatively correlate with cell proliferation in BrCa cells, i.e. rapidly dividing tumour cells have the lowest number of IR events. Aberrant RNA-binding protein expression and changes in tissue composition are among the causes of aberrantly decreasing IR in BrCa.ConclusionsOur results suggest that IR should be considered for therapeutic manipulation in BrCa patients with aberrantly low IR levels and that further work is needed to understand the cause and impact of high IR in other tumour types.

【 授权许可】

CC BY   
© The Author(s) 2022

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