ERBB2 activation leads to an anti-oncogenic signalling

Approximately 20% of breast cancers display ERBB2 (HER2) gene amplification and/or protein overexpression. In cancer cells, ERBB2 can function both in the homodimeric and het- erodimeric form. Moreover, it represents the preferred partner of other members of the ERBB receptor family. Strikingly, ERBB2-containing heterodimers are more oncogenic than other ERBB combinations, mostly by promoting cell proliferation via ERK activation and cell survival via the AKT pathway. AKT signalling plays a fundamental role in driving breast carcinogenesis and is downmodulated in response to the binding of the humanized therapeutic antibody Tras- tuzumab (TZ) to ERBB2. How ERBB2 differentially modulates AKT in ERBB2-overexpressing BrCa cells upon TZ treatment, remain unclear. Our findings show that TZ treatment of ERBB2- positive breast cancer cell lines triggers the homodimerization and the activation of ERBB2, leading to an previously unidentified signalling cascade causing an ERK-dependent AKT de- phosphorylation, via PP2A Ser/Thr phosphatases. The immunophilin Cyclophilin A (CyPA) plays a key role in this pathway, as a negative modulator of AKT de-phosphorylation, by com- peting with PP2A phosphatases for binding to AKT. Upon TZ treatment ERK promotes CyPA redistribution to ERBB2, allowing the binding of PP2A to phospho-AKT. Finally, we report that CyPA silencing reverts TZ-resistant human ERBB2-positive breast cancer cell lines to a TZ- responsive state. In conclusion, we show that in breast cancer cells TZ promotes ERBB2 activa- tion, working as a “putative” ligand of the receptor, and that the outcome of the ERBB2 activity depends on the dimerization status: pro-oncogenic in the hetero- and anti-proliferative in the homodimeric form. This work was supported by grants from MIUR PRIN-2012, Compagnia San Paolo (grant number 2011.1172 and 2015.0323) to CT, and from AIRC (IG number 12035 and 17109) to CT and GT.