Awards Session
AB069. SOH22ABS209. The epitranscriptomic landscape in estrogen receptor (ER)-positive breast cancer disease progression
Stephen Keelan1,2, Mihaela Ola1, Sara Charmsaz1, Sinead Cocchiglia1,2, Karen Crowley1, Siobhan Purcell1, Fiona Bane1,2, Aisling Hegarty1,2, Ben Doherty1, Katherine Sheehan1,3, Lance Hudson2, Nicola Cosgrove1, Benjamin Roux1, Muriel Laine4, Geoffrey Greene4, Damir Vareslija1,2, Arnold Hill1,2, Leonie Young1,2
1Department of Surgery, RCSI University of Medicine and Health Sciences, Endocrine Oncology Research Group, Dublin, Ireland;
2Department of Surgery, Beaumont Hospital, Dublin, Ireland;
3Department of Pathology, Beaumont Hospital, Dublin, Ireland;
4Department of Biochemistry and Molecular Biology, The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, USA
Background: Breast cancer is a highly heterogeneous and progressive disease and is a major cause of mortality worldwide. Significant clinical advances require detailed understanding of tumour cell adaptability and progression to metastases. To understand the role of the epitranscriptome in tumorigenesis we mapped dynamic global Ribonucleic acid (RNA) epitranscriptomic in progressive estrogen receptor (ER)-positive disease.
Methods: To define the m6A methyl landscape, MeRIP-sequencing was performed in models of breast cancer disease progression. The global proteome was mapped using mass spectrometry, allowing validation of the functional output of methyl modifications. Using a large patient cohort (n=920) the effect of key RNA-methyl machinery, fat mass and obesity-associated protein (FTO), ALKBH5, METTL3 and METTL14 on overall survival and progression-free survival was assessed. Functional assays and PDX-ex-vivo and organoid models were used to investigate the translational efficacy of targeting key RNA-methyl modulators in the management of advanced breast cancer.
Results: Global gains in m6A methylation were observed with disease progression. Integration of the methylome and proteome revealed a strong correlation of perturbations in stem cell differentiation pathways. Notably RNA demethylator FTO, mediates the expression of stem cell genes KLF4, SOX2 and SOX4. FTO associated with poor overall (P=0.04) and progression-free survival (P=0.02) in breast cancer patients. Pharmacological inhibition of FTO reduced stem cell gene expression and tumour cell growth in patient brain metastatic models.
Conclusions: We provide evidence that dysregulated m6A modifications are a pertinent feature of progressive disease. We report that FTO an RNA methyl ‘eraser’ can drive tumorigenesis through modulation of stem cell differentiation. Targeting FTO represents a promising novel approach to managing advanced breast cancer.
Keywords: Breast cancer; epitranscriptome; fat mass and obesity-associated protein (FTO); Ribonucleic acid methylation (RNA methylation); stem cell
Acknowledgments
Funding: None.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
doi: 10.21037/map-22-ab069
Cite this abstract as: Keelan S, Ola M, Charmsaz S, Cocchiglia S, Crowley K, Purcell S, Bane F, Hegarty A, Doherty B, Sheehan K, Hudson L, Cosgrove N, Roux B, Laine M, Greene G, Vareslija D, Hill A, Young L. AB069. SOH22ABS209. The epitranscriptomic landscape in estrogen receptor (ER)-positive breast cancer disease progression. Mesentery Peritoneum 2022;6:AB069.
