Towards resolution of the intron retention paradox in breast cancer

Shah, JS; Milevskiy, MJG; Petrova, V; Au, AYM; Wong, JJL; Visvader, JE; Schmitz, U; Rasko, JEJ

Author(s): Shah, JS; Milevskiy, MJG; Petrova, V; Au, AYM; Wong, JJL; Visvader, JE; Schmitz, U; Rasko, JEJ;
Details: Publication Year 2022-12-29,Volume 24,Issue #1,Page 100
Journal Title: Breast Cancer Research
Abstract: BACKGROUND: After 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. METHODS: In 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. RESULTS: Strikingly, 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. CONCLUSIONS: Our 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.
Keywords: Humans; Female; *Breast Neoplasms/pathology; Introns/genetics; Breast/pathology; Cell Proliferation; Adipocytes; Alternative splicing; Cancer transcriptomics; Luminal B breast cancer; Patient stratification
Research Division(s): Cancer Biology And Stem Cells
PubMed ID: 36581993
Publisher's Version: https://doi.org/10.1186/s13058-022-01593-1
Open Access at Publisher's Site: https://doi.org/ 10.1186/s13058-022-01593-1
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Shah et al Breast Cancer Research 2022.pdf - (2.51MB, application/pdf)

Creation Date: 2023-01-30 02:59:54

Last Modified: 2023-01-30 03:06:55