CDK4 and breast cancer: In ER+ breast cancer, combined inhibition of mTOR and CDK4/6 may result in more complete suppression of E2F-dependent transcription [35] and in our study palbociclib-resistant cell lines demonstrated a loss of RB1 expression and increase of Cyclin E1, both of which can enhance E2F activity and likely contributed to resistance to CDK4/6 inhibition.