Epigenetic Modulation of BRCA1 and CCND2 in Breast Cancer Cells by curcumin, lycopene and capsaicin: A Comparative Analysis with 5-Azacytidine

Breast cancer is characterised by aberrant DNA methylation that silences tumour suppressor genes. While synthetic DNA methyltransferase inhibitors (DNMTi) such as 5-Azacytidine (5-AZA) have shown clinical efficacy, interest is growing in natural compounds as potential epigenetic modulators. This study aims to examine the possible hypomethylating effects of curcumin, lycopene, and capsaicin on BRCA1 and CCND2 genes and, hence, their expression in MCF-7 cells, compared to the standard demethylating agent 5-AZA. Using quantitative PCR and methylation-specific PCR (MSP), we assessed changes in mRNA expression and promoter methylation, alongside evaluating the expression of DNMT1, DNMT3A, and DNMT3B. 5-AZA significantly reduced CCND2 methylation and increased its expression, consistent with known DNMTi activity, but paradoxically increased BRCA1 methylation. Curcumin downregulated DNMT3A and reduced methylation of both genes, yet failed to induce gene expression. Lycopene downregulated all three DNMTs but increased methylation and silencing of both genes, indicating a complex regulatory mechanism. Capsaicin markedly upregulated DNMT3A/3B, resulting in hypermethylation and suppression of BRCA1 and CCND2. These findings reveal that natural compounds exhibit diverse and gene-specific epigenetic effects, with curcumin showing partial DNMT inhibition, lycopene eliciting paradoxical hypermethylation despite DNMT suppression, and capsaicin acting as a potential hypermethylating agent. This study emphasises the nuanced role of natural products in epigenetic therapy and supports further investigation into their combinatorial or dose-dependent application in the management of breast cancer.