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The aim of the present study was to investigate how the miR-451 a can regulate resistance to tamoxifen(TAM) of breast cancer cells by modulating the expression of estrogen receptor α(ERa) and 14-3-3ζ.The effects of miR-451 a and R18,an inhibitory peptide of 14-3-3 protein,on growth and apoptosis of MCF-7 and LCC2 cells were detected by MTT assay,AnnexinV-FITC binding assay,and Hochest 33258 staining.The expressions of ERa,14-3-3ζ,and miR-451 a were measured by qRT-PCR and Western blot analysis.The interaction of 14-3-3ζ and ERa was investigated by co-immunoprecipitation.It was shown that over-expression of miR-451 a can enhance the TAM sensitivity in MCF-7 and LCC2 cells.Opposite effects were elicitedby knocking down miR-451 a in these cells.Our results also showed that the TAM treatment could up-regulate 14-3-3ζ,and down-regulate ERa expression in a time-dependent manner.The mRNA expression of 14-3-3ζ and miR-451 a were inversely correlated,while the mRNA expression of ERa and miR-451 a were positively correlated.Furthermore,the 14-3-3ζ protein and ERa protein can interact.Over-expression of miR-451 a can decrease 14-3-3ζ expression,and increase ERa expression,which consequently suppressed cell proliferation,increased apoptosis,and reduced activation of p-AKT and p-mTOR.R18 can significantly decrease cell prolif-eration,and increase apoptosis.R18 and si 14-3-3ζ can inhibit the effects of down-regulation of ERa after knocking down of miR-451 a.In conclusion,overexpression of miR-451 a can enhance the sensitivity of breast cancer cells to TAM by down-regulating 14-3-3ζ and up-regulating ERa,which suggested it to be a potential target for restoring ERa expression and reversing resistance to antiestrogen therapy.