Functional and clinical significance of the RNA m6A methyltransferase complex in breast cancer.

TitleFunctional and clinical significance of the RNA m6A methyltransferase complex in breast cancer.
Publication TypeJournal Article
Year of Publication2025
AuthorsHarris AE, Lothion-Roy J, Thompson RL, Haque M, Woodcock CL, Alsaleem MA, Dean A, Kariri Y, Toss MS, Gudas LJ, Green AR, Allegrucci C, Davis MB, Irshad S, Park K-H, Madhusudan S, Fray RG, Jeyapalan JN, Rutland CS, Rakha EA, Mongan NP
JournalNPJ Breast Cancer
Volume11
Issue1
Pagination147
Date Published2025 Nov 27
ISSN2374-4677
Abstract

The RNA modification N6-methyladenosine (m6A) plays a key role in RNA processing. It is catalysed by the RNA methyltransferase complex (MTC) which includes METTL3, METTL14 and CBLL1. Recently, a METTL3 inhibitor demonstrated promising preclinical results in several cancer types, yet the therapeutic potential of targeting m6A in breast cancer (BCa) remains poorly understood. Utilising a large BCa cohort, we identified that increased METTL14 and CBLL1 expression was associated with a more favourable prognosis, whereas increased METTL3 expression was associated with poorer patient outcomes in Triple Negative BCa (TNBC). Using siRNA depletion, we identified distinct METTL3, METTL14 and CBLL1 regulated gene networks in BCa cell lines. METTL3 inhibition reduced proliferation and invasion of BCa cell lines and induced an immune activation transcriptional signature. These results provide insight into the clinical functions of METTL3, METTL14 and CBLL1 in BCa and support the therapeutic potential of targeting METTL3 in BCa, particularly in TNBC.

DOI10.1038/s41523-025-00861-5
Alternate JournalNPJ Breast Cancer
PubMed ID41310336
PubMed Central IDPMC12722736
Grant ListBB/T008369/1; BB/I024291/1 / / BBSRC /
36565532 / / philanthropic donation /