ESR1 and breast cancer: Here, we used an ER+ve model of spontaneous breast cancer metastasis from the mammary fat pad to bone and a TNBC model of metastatic outgrowth in bone (intracardiac route), to provide the first demonstration that palbociclib inhibits both ER+ve and TNBC growth in murine bone and to establish potential mechanisms that promote CDK4/6 targeted drug insensitivity following treatment breaks.