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Estrogen receptor-α (ERα) promotes proliferation of breast cancer cells, whereas tumor suppressor protein p53 impedes proliferation of cells with genomic damage. Whether there is a direct link between these two antagonistic pathways has remained unclear. Here we report that ERα binds directly to p53 and represses its function. The activation function-2 (AF-2) domain of ERα and the C-terminal regulatory domain of p53 are necessary for the interaction. Knocking down p53 and ERα by small interfering RNA elicits opposite effects on p53-target gene expression and cell cycle progression. Remarkably, ionizing radiation that causes genomic damage disrupts the interaction between ERα and p53. Ionizing radiation together with ERα knock down results in additive effect on transcription of endogenous p53-target gene p21 (CDKN1) in human breast cancer cells. Our findings reveal a novel mechanism for regulating …