Validating raloxifene-mediated restoration of DNMT-TET epigenetic balance in breast and lung cancer.

The aberrant DNA methylation is a characteristic feature of solid tumours, but the imbalance of DNA methyltransferases and demethylases has not been studied at the network level across breast and lung cancers. To determine the role of the DNMT-TET axis and assess the therapeutic potential of raloxifene as an epigenetic rebalancer, we undertook transcriptomic profiling of large patient cohorts in The Cancer Genome Atlas (TCGA) breast invasive carcinoma (TCGA-BRCA) and lung adenocarcinoma (TCGALUAD). In both tumour types, DNMT1 was consistently over-expressed, while the TET family demethylases (TET1, TET2, TET3) were coordinately down-regulated, resulting in a striking increase in the DNMT/TET balance index and a transcriptional programme that is biased towards CpG hypermethylation. Subtype stratifications revealed the highest distortion of this axis in the aggressive phenotypes, such as triple-negative breast cancer. Next, we examined raloxifene-treated models and found that DNMT1 silencing and raloxifene treatment were accompanied by partial re-expression of the TET gene, consistent with a directional re-equilibration at the loci examined rather than uniform global hypomethylation, a distinction that remains to be confirmed at genome scale.Network-level visualisation of the DNMT-TET signature revealed a consistent, directional raloxifene-associated shift at the regulatory loci examined; the present data do not establish genome-wide specificity, which will require methylome-scale profiling. Together, our data represent a molecular signature for breast and lung tumorigenesis, the DNMT-TET disequilibrium, and place raloxifene in a dual SERM-epigenetic context. These results support the concept of precision oncology in which reversible, locus-directed methylation changes are combined with endocrine modulation to target hormone-responsive and epigenetically biased cancers.