Oncotarget

Research Papers:

Cooperative but distinct early co-signaling events originate from ERBB2 and ERBB1 receptors upon trastuzumab treatment in breast cancer cells

Paola Bagnato, Alessia Castagnino, Katia Cortese, Maria Bono, Silvia Grasso, Grazia Bellese, Tiziana Daniele, Richard Lundmark, Paola Defilippi, Patrizio Castagnola _ and Carlo Tacchetti

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Oncotarget. 2017; 8:60109-60122. https://doi.org/10.18632/oncotarget.17686

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Abstract

Paola Bagnato1,*, Alessia Castagnino1,*, Katia Cortese1,*, Maria Bono1, Silvia Grasso2, Grazia Bellese1, Tiziana Daniele3, Richard Lundmark4, Paola Defilippi2, Patrizio Castagnola5 and Carlo Tacchetti1,3

1DIMES, Dipartimento di Medicina Sperimentale, Anatomia Umana, Università di Genova, Genova, Italy

2Molecular Biotechnology Centre and Department of Genetics, Biology and Biochemistry, Torino, Italy

3San Raffaele Scientific Institute, Experimental Imaging Centre, Milan, Italy

4Department of Medical Biochemistry and Biophysics, Umea University, Umea, Sweden

5Department of Integrated Oncological Therapies, IRCCS AOU - San Martino - IST, Largo Rosanna Benzi, Genova, Italy

*These authors have contributed equally to this work

Correspondence to:

Patrizio Castagnola, email: [email protected]

Carlo Tacchetti, email: [email protected]

Keywords: ERBB2, trastuzumab, circular dorsal ruffles, ERBB1, breast cancer

Received: November 15, 2016     Accepted: April 03, 2017     Published: May 08, 2017

ABSTRACT

ERBB2 receptor belongs to the ERBB tyrosine kinase receptor family. At variance to the other family members, ERBB2 is a constitutively active orphan receptor. Upon ligand binding and activation, ERBB receptors form homo- or hetero-dimers with the other family members, including ERBB2, promoting an intracellular signaling cascade. ERBB2 is the preferred dimerization partner and ERBB2 heterodimers signaling is stronger and longer acting compared to heterodimers between other ERBB members. The specific contribution of ERBB2 in heterodimer signaling is still undefined.

Here we report the formation of circular dorsal ruffles (CDRs) upon treatment of the ERBB2-overexpressing breast cancer cell lines SK-BR-3 and ZR751 with Trastuzumab, a therapeutic humanized monoclonal antibody directed against ERBB2. We found that in SK-BR-3 cells Trastuzumab leads to surface redistribution of ERBB2 and ERBB1 in CDRs, and that the ERBB2-dependent ERK1/2 phosphorylation and ERBB1 expression are both required for CDR formation. In particular, in these cells CDR formation requires activation of both the protein regulator of actin polymerization N-WASP, mediated by ERK1/2, and of the actin depolymerizing protein cofilin, mediated by ERBB1. Furthermore, we suggest that this latter event may be inhibited by the negative cell motility regulator p140Cap, as we found that p140Cap overexpression led to cofilin deactivation and inhibition of CDR formation.

In conclusion, here we show for the first time an ERBB2-specific signaling contribution to an ERBB2/ERBB1 heterodimer, in the activation of a complex biological process such as the formation of CDRs.


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