HER2-targeting Antibodies Modulate the Cyclin-dependent Kinase Inhibitor p27Kip1 via Multiple Signaling Pathways

Abstract

Anti-HER2 antibody trastuzumab is emerging as a frontline therapy for patientswith metastatic breast cancers that overexpress HER2. Understanding the molecularmechanisms by which the antibody inhibits tumor growth should permit the design ofeven more effective trastuzumab-based protocols. Several groups including our own havedemonstrated that induction of cyclin-dependent kinase (CDK) inhibitor p27Kip1 protein isone of the key mechanisms of action of HER2-targeting antibodies. In this review, wediscuss currently available data regarding the multiple signaling targets and pathways bywhich HER2-targeting antibodies upregulate p27Kip1 protein in breast cancer cells thatoverexpress HER2. Anti-HER2 antibodies inhibits HER2-mediated signaling in cancercells, ultimately upregulating the levels and activity of p27Kip1 protein. At least sixsignaling targets and pathways are modulated by trastuzumab. By inhibiting CDK2 anddecreasing Thr187 phosphorylation of p27Kip1, trastuzumab abrogates targeting of SCFubiquitinE3 ligase and minimizes proteasome degradation of p27Kip1. By inhibiting AKTand human kinase interacting stathmin (hKIS), trastuzumab blocks Thr157-, Thr198-, andSer10-induced p27Kip1 translocation from the nucleus to the cytosol, which increases theinhibitory effect of p27Kip1. By inhibiting Jun activation domain-binding protein 1 (Jab1)trastuzumab increases nuclear retention of p27Kip1. By inhibiting cyclin D and c-Myc,trastuzumab releases the sequestrated p27Kip1 protein from cyclin D-CDK4/6 complexesand increase the effect of p27Kip1 on CDK2-cyclin E complexes. By stimulating minibrainrelated kinase (MIRK), trastuzumab stabilizes p27Kip1 in the nucleus, which increasesinhibitory action of p27Kip1 on CDK2. The targets and pathways affected by trastuzumab work in concert to maximize the expression and inhibitory effect of p27Kip1, which leadsto cell cycle G1 arrest and growth inhibition.