First evidences that Resveratrol through p53/Sin3/HDAC1 complex phosphorylation inhibits ESR1 gene expression via p38MAPK signalling.

Abstract

Agents to counteract acquired resistance to hormonal therapy for breast cancer would substantially enhance the long-term benefits of hormonal therapy. In the present study we demonstrate how resveratrol (Res) inhibits human breast cancer cell proliferation including MCF-7 tamoxifen-resistant cells. We show that Res, through p38MAPK phosphorylation, causes induction of p53 which recruits at the ER alpha proximal promoter, leading to an inhibition of ER alpha expression in terms of mRNA and protein content. These events appear specifically p53-dependent, since it is drastically abrogated with p53 targeting siRNA. Co-immunoprecipitation of nuclear extracts showed specific interaction between p53, the Sin3A corepressor and HDAC1 which was phosphorylated. In the presence of a specific p38MAPK inhibitor the above described interactions were prevented. The enhancement of the tripartite complex p53/Sin3A/HDAC1 with Res treatment was confirmed by ChIP analyses, with a concomitant release of Sp1 and RNA polymerase II, thereby inhibiting the cell transcriptional machinery. The persistence of such effects in MCF-7 tamoxifen resistant cells at a higher extent than parental MCF-7 cells, addresses how Res may be considered as useful pharmacological tool to be exploited in the adjuvant settings for treatment of breast cancer developing hormonal resistance.