Oncology Abstracts

Endocrine therapy including tamoxifen and aromatase inhibitors (AIs) are standard therapy for ER- positive breast cancer and despite its success a significant number of patients develop resistance to treatment. Transcriptional and epigenetic re-programing including DNA and RNA methylation develops with high frequency in response to therapy. Global DNA and RNA multi-omic studies have been utilized to understand the altered transcriptome of endocrine resistant breast cancer cell models and we have uncovered alterations in oncogenic, differentiation and kinase signalling pathways. RNA modifications including RNA-methylation play an important role in many biological processes. The RNA methyl mark N6-methyladenosine (m6A) is the main transcriptional modification event in RNA-methylation. Studies show that m6A modifications are catalysed through m6A ‘writers’ (METTL3, METTL14 and WTAP) and RNA-methylation is inhibited through m6A ‘erasers’ (FTO, ALKBH5). The role of RNA-machinery in breast cancer is largely unknown. Here we determine the role of RNA-methylation machinery in development of endocrine resistant metastatic breast cancer. The role of FTO and METTL3, the key players in RNA-methylation was investigated in a cohort of breast cancer patients where we observed that METTL3 (P=0.0242) is associated with prolonged disease-free- survival and FTO (P=0.0182) is associated with reduced disease-free-survival (n=870). Moreover, using gene expression analysis comparing patients with disease-recurrence versus those with no recorded relapse we have observed elevated levels of FTO and significant elevation of ALKBH5 (P=0.0068) in patients with subsequent disease-recurrence (n=24). Identifying FTO as a contributor to the metastatic progression we have analysed the role of FTO in models of endocrine resistant and sensitive breast cancer showing, elevated levels of FTO in endocrine resistant cells (LY2, LetR cells) in comparison to endocrine sensitive (MCF7 cells). Furthermore we have observed FTO to drive mammosphere formation, anchorage independent growth and proliferation all of which are hallmarks of metastasis. In summary, this study identifies the m⁶A mRNA methylation machinery as a potential therapeutic target for breast cancer progression that needs exploring.