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An epigenetic component, especially aberrant DNA methylation pattern, has been shown to be frequently involved in sporadic breast cancer development. A growing body of literature demonstrates that combination of agents, i.e. nucleoside analogues with dietary phytochemicals, may provide enhanced therapeutic effects in epigenetic reprogramming of cancer cells. Clofarabine (2-chloro-2&#8242;-fluoro-2&#8242;-deoxyarabinosyladenine, ClF), a second-generation 2&#8242;-deoxyadenosine analogue, has numerous anti-cancer effects, including potential capacity to regulate epigenetic processes. Our present study is the first to investigate the combinatorial effects of ClF (used at IC₅₀ concentration) with epigallocatechin-3-gallate (EGCG, tea catechin) or genistein (soy phytoestrogen), at physiological concentrations, on breast cancer cell growth, apoptosis, and epigenetic regulation of retinoic acid receptor beta (<i>RARB</i>) transcriptional activity. In MCF7 and MDA-MB-231 cells, <i>RARB</i> promoter methylation and expression of <i>RARB</i>, modifiers of DNA methylation reaction (<i>DNMT1</i>, <i>CDKN1A</i>, <i>TP53</i>), and potential regulator of <i>RARB</i> transcription, <i>PTEN</i>, were estimated using methylation-sensitive restriction analysis (MSRA) and quantitative real-time polymerase chain reaction (qPCR), respectively. The combinatorial exposures synergistically or additively inhibited the growth and induced apoptosis of breast cancer cells, followed by <i>RARB</i> hypomethylation with concomitant multiple increase in <i>RARB</i>, <i>PTEN</i>, and <i>CDKN1A</i> transcript levels. Taken together, our results demonstrate the ability of ClF-based combinations with polyphenols to promote cancer cell death and reactivate DNA methylation-silenced tumor suppressor genes in breast cancer cells with different invasive potential.