High intensity and sustained activation of ERK1/2 can induce high expression of p21.52 At the same time, GPR30/EGFR/ERK1/2 also mediated the phosphorylation of p53 at Ser 15 in ER− breast cancer cells, which might be induced by the direct interaction of ERK and p53 on Ser 15.53 Phosphorylation of p53 at Ser 15 has been shown to be involved in activating p5343 and activating the transcription of p21.54 Collectively, our data revealed that p53, EGFR/ERK1/2, and their cross-talk upregulated the expression of p21 and mediated the growth arrest effects. Here, GPER1 is linked to breast cancer.