Discoidin domain receptor 1 modulates insulin receptor signaling and biological responses in breast cancer cells

// Veronica Vella 1, * , Roberta Malaguarnera 2, * , Maria Luisa Nicolosi 2 , Chiara Palladino 2 , Cristina Spoleti 2 , Michele Massimino 3 , Paolo Vigneri 3 , Michele Purrello 4 , Marco Ragusa 4 , Andrea Morrione 5 and Antonino Belfiore 2 1 School of Motor Sciences, Faculty of Human and Social Sciences, Kore University of Enna, Enna, Italy 2 Endocrinology, Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy 3 Department of Clinical and Experimental Medicine, Faculty of Medicine, University of Catania, Catania, Italy 4 Department of Biomedical and Biotechnological Sciences, Unit of BioMolecular, Genome, and Complex System BioMedicine, University of Catania, Catania, Italy 5 Department of Urology and Biology of Prostate Cancer Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA * These authors have contributed equally to this work Correspondence to: Antonino Belfiore, email: belfiore@unicz.it Keywords: insulin receptor, insulin receptor isoforms, DDR1, breast cancer Received: February 23, 2017 Accepted: April 14, 2017 Published: May 19, 2017 ABSTRACT The fetal isoform A of the insulin receptor (IR-A) is frequently overexpressed in a variety of malignancies including breast cancer. IR overexpression has a recognized role in cancer progression and resistance to anticancer therapies. In particular, IR-A has a peculiar mitogenic potential and is activated not only by insulin but also by IGF-2. Previously, we identified discoidin domain receptor 1 (DDR1) as a new IR-A interacting protein. DDR1, a non-integrin collagen tyrosine kinase receptor, is overexpressed in several malignancies and plays a role in cancer progression and metastasis. We now evaluated whether DDR1 is able to exert a role in breast cancer biology by functionally cross-talking with IR. In MCF-7 human breast cancer cells, IR and DDR1 co-immunoprecipitated and co-localized after insulin or IGF-2 stimulation. In a panel of breast cancer cells, DDR1 knockdown by specific siRNAs markedly inhibited IR downstream signaling as well as proliferation, migration and colony formation in response to insulin and IGF-2. These effects were accompanied by reduction of IR protein and mRNA expression, which involved both transcriptional and post-transcriptional effects. DDR1 overexpression elicited opposite effects. Bioinformatics analysis of public domain databases showed that IR and DDR1 co-expression significantly correlates with several clinically relevant histopathological and molecular features of human breast carcinomas. These findings demonstrate that, in human breast cancer cells, DDR1 regulates IR expression and ligand dependent biological actions. This novel functional crosstalk is likely clinically relevant and may become a new molecular target in breast cancer.