Functional and clinical significance of the RNA m6A methyltransferase complex in breast cancer
The RNA modification N<sup>6</sup>-methyladenosine (m<sup>6</sup>A) 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 m<sup>6</sup>A 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.
Authors
- Corinne L. Woodcock (ORCID: https://orcid.org/0000-0001-6369-0182)
- Rupert G. Fray (ORCID: https://orcid.org/0000-0002-3935-8945)
- Michael S. Toss (ORCID: https://orcid.org/0000-0002-9077-3984)
- Emad A. Rakha (ORCID: https://orcid.org/0000-0002-5009-5525)
- Kyong Hwa Park (ORCID: https://orcid.org/0000-0002-2464-7920)
- Maria Haque
- Catrin S. Rutland (ORCID: https://orcid.org/0000-0002-2009-4898)
- Alexander Dean
- Lorraine J. Gudas (ORCID: https://orcid.org/0000-0003-3115-4777)
- Melissa B. Davis (ORCID: https://orcid.org/0000-0002-6124-6923)
- Yousif A. Kariri (ORCID: https://orcid.org/0000-0002-2507-2292)
- Jennie Jeyapalan
- Jennifer Lothion‐Roy (ORCID: https://orcid.org/0000-0002-8602-7006)
- Mansour Abdulaziz Alsaleem (ORCID: https://orcid.org/0000-0002-7689-2493)
- Sheeba Irshad (ORCID: https://orcid.org/0000-0002-4419-7162)
- Cinzia Allegrucci (ORCID: https://orcid.org/0000-0001-8517-2423)
- Nigel P. Mongan (ORCID: https://orcid.org/0000-0001-5438-1126)
- Anna E. Harris (ORCID: https://orcid.org/0000-0003-4153-1652)
- Andrew R. Green (ORCID: https://orcid.org/0000-0002-0488-5913)
- Madhusudhan Srinivasan (ORCID: https://orcid.org/0000-0001-5676-4219)
- Rachel L. Thompson (ORCID: https://orcid.org/0009-0001-4974-0355)
Institutions
- Nottingham University Hospitals NHS Trust (GB)
- University of Nottingham (GB)
- Qassim University (SA)
- Guy's and St Thomas' NHS Foundation Trust (GB)
- Cornell University (US)
- Shaqra University (SA)
- Sheffield Teaching Hospitals NHS Foundation Trust (GB)
- Korea University (JP)
- Weill Cornell Medicine (US)
- Morehouse School of Medicine (US)
Publication Details
- Journal
- npj Breast Cancer
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1038/s41523-025-00861-5
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00