Epigenetic reactivation of p21CIP1/WAF1 and KLOTHO by a combination of bioactive dietary supplements is partially ERα-dependent in ERα-negative human breast cancer cells

•Dietary combinations of DNMT and HDAC inhibitors induce significant cell cycle arrest than the standard inhibitors.•Combinations of GTPs and SFN reactivate tumor suppressor genes (TSGs) in MDA-MB-231 cells.•The reactivations of TSGs are mainly mediated through the active chromatin modifications.•Reactivation of TSGs is partially dependent on estrogen receptor-α (ERα) reactivation in ERα-negative breast cancer cells.•The reactivation of silenced ERα sensitizes cells for the tamoxifen therapy.

Available treatment strategies against estrogen receptor (ER)-negative breast cancer patients are limited due to their poor response to hormonal therapy. We have shown previously that the combinations of green tea polyphenols (GTPs), a dietary DNA methyltransferase inhibitor, and sulforaphane (SFN), a dietary histone deacetylase inhibitor, reactivate ERα expression in ERα-negative MDA-MB-231 cells. Here, we investigated the functional significance of ERα reactivation in the reactivation of silenced tumor suppressor genes (TSGs) in ERα-negative human breast cancer cells. We found that the treatment of MDA-MB-231 cells with the combinations of GTPs and SFN leads to the reactivation of silenced TSGs such as p21CIP1/WAF1 and KLOTHO through active chromatin modifications. Further, GTPs- and SFN-mediated reactivation of TSGs was, at least in part, dependent on ERα reactivation in ERα-negative MDA-MB-231 cells. Collectively, our findings suggest that a novel combination of bioactive dietary supplements could further be explored as an effective therapeutic option against hormonal refractory breast cancer.

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