ESR1 and breast cancer: Normally, mitotic signals drive the expression of cyclin D, which associates with the G1 kinases, CDK4/6, leading to the phosphorylation of Rb, activation of the transcriptional activity of E2F, and the subsequent generation of the S phase kinase, CDK2/cyclin E. In breast cancer, ER+ in particular, multiple signaling pathways converge to target cyclin D (17, 18).