These seminal studies have open the way to the testing of specific CDK4 and CDK6 small molecule inhibitors (hereafter CDK4/6i) to treat human tumors, in particular estrogen receptor positive (ER+) breast cancers, in which their use, combined with hormonal therapies, has proved highly effective in the control of disease progression [14,15,16,17]. Here, ESR1 is linked to breast cancer.