Abstract 3813: PHB2 inactivation by AKAP-BIG3 is required for progression of HER2-overexpressing breast cancer

Abstract

Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer is linked to aggressive tumor behavior and a poorer prognosis. Anti-HER2 monoclonal antibody, trastuzumab extends the overall survival of patients with HER2-overexpressing breast cancer, but resistance to trastuzumab and/or other HER2-targeted therapies remains a serious clinical problem. Our previous studies demonstrated that Brefeldin A-Inhibited Guanine nucleotide-exchange protein 3 (BIG3), which is exclusively overexpressed in the majority of breast cancers, functions as a cancer specific A-kinase anchoring protein that binds protein kinase A (PKA) and protein phosphatase 1 (PP1Cα), thereby inactivating prohibitin2 (PHB2) suppressive activity through its dephosphorylation on Ser39. We further developed dominant-negative stapling peptide (stERAP), which is designed to specifically disrupt binding of BIG3-PHB2 complex and improve duration of their anti-tumor effects. Here we newly report that stERAP has significant suppressive effects on the HER2 signaling network by activating the tumor suppressive ability of PHB2. stERAP resulted in intrinsic PHB2 release from BIG3, followed by rapid phosphorylation on Ser39, Thr42 and Thr169 via PKCα, TTK and MK5, respectively. Importantly, PHB2 released from BIG3 by stERAP treatment translocated into nucleus, followed by acting as a transcriptional co-repressor by recruiting HDAC1 and NcoR through its Ser39-phosphorylation. More importantly, we observed that serine/threonine phosphorylations of PHB2 are necessary for disruption of HER2-HER3 hetero-dimerization and NF-κB signalling activation which are associated with acquired resistance to trastuzumab. We demonstrated that weekly treatment of stERAP completely suppressed the proliferation of trastuzumab-resistant HER2-positive breast cancer cells in vitro and in vivo . We are currently examining the association of both BIG3 overexpression and PHB2 dephosphorylation with poor prognosis of patients with HER2-positive breast cancers by immunohistochemical staining, and will report these results at this meeting. We demonstrated for the first time that PHB2 inactivation by the AKAP-BIG3 (BIG3/PKA/PP1Cα tri-complex) is required for oncogenic HER2 signalling activation in breast cancer cells, and stERAP may be a promising anti-cancer drug for trastuzumab-resistant breast cancer. Citation Format: Tetsuro Yoshimaru, Yosuke Matsushita, Mitsunori Sasa, Yasuo Miyoshi, Toyomasa Katagiri. PHB2 inactivation by AKAP-BIG3 is required for progression of HER2-overexpressing breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3813.