CDK4 and breast cancer: Interestingly, the five novel candidates to be targeted in de novo trastuzumab resistant breast cancer have one feature in common: they all either directly (ER-α, c-MYC and CDK4) or indirectly (Cyclin D1 and Cyclin E1) regulate the p27 protein, which plays a key role also in acquired trastuzumab resistance [38].