RNA methylation and breast cancer: insights into m6A, m7G and m5C.

Abstract

Breast cancer remains the most commonly diagnosed cancer in female worldwide, marked by its molecular diversity and complex subtypes. Despite progress in targeted therapies, tumor heterogeneity and treatment resistance continue to present major challenges. Recent studies emphasize the crucial role of RNA modifications in cancer biology, with nearly 200 distinct modifications identified. Among these, methylation is particularly significant, with methylation-related factors emerging as key regulators of RNA metabolism, influencing cancer progression, metastasis, and treatment resistance. This review focuses on the roles of key RNA methylation in breast cancer, particularly N6-methyladenosine (m6A), N7-methylguanosine (m7G), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N3-methylcytidine (m3C). We examine the functions of m6A "writers" like METTL3 and METTL14, and "readers" such as the YTH domain family in modulating tumor behavior. Dysregulation of m6A "erasers" like FTO and ALKBH5 are noticed too, highlighting their impact on cancer stem cell phenotypes, chemoresistance, and immune evasion. Additionally, the role of m7G modifications in mRNA stability and translation, facilitated by METTL1/WDR4 and RNMT, is discussed as a potential therapeutic target. The involvement of m5C, m1A, and m3C modifications, particularly those mediated by NSUN2 and NSUN6, in breast cancer tumorigenesis and prognosis is also reviewed. Despite coding RNAs, the interplay between these RNA methylations and non-coding RNAs, such as lncRNAs and miRNAs, is explored, shedding light on their roles in cancer cell proliferation, invasion, and immune response modulation. This review highlights the potential of RNA methylations as novel therapeutic targets in breast cancer, offering insights for precision medicine and improved patient outcomes.