Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells
Veronica Vella,
Marika Giuliano,
Alessandro La Ferlita,
Michele Pellegrino,
Germano Gaudenzi,
Salvatore Alaimo,
Michele Massimino,
Alfredo Pulvirenti,
Alessandra Dicitore,
Paolo Vigneri,
Giovanni Vitale,
Roberta Malaguarnera,
Andrea Morrione,
Andrew H. Sims,
Alfredo Ferro,
Marcello Maggiolini,
Rosamaria Lappano,
Ernestina Marianna De Francesco,
Antonino Belfiore
Affiliations
Veronica Vella
Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
Marika Giuliano
Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
Alessandro La Ferlita
Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, 95131 Catania, Italy
Michele Pellegrino
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
Germano Gaudenzi
Laboratory of Geriatric and Oncologic Neuroendocrinology Research, Istituto Auxologico Italiano, IRCCS, 20095 Cusano Milanino, Italy
Salvatore Alaimo
Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, 95131 Catania, Italy
Michele Massimino
Oncology Unit, Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy
Alfredo Pulvirenti
Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, 95131 Catania, Italy
Alessandra Dicitore
Laboratory of Geriatric and Oncologic Neuroendocrinology Research, Istituto Auxologico Italiano, IRCCS, 20095 Cusano Milanino, Italy
Paolo Vigneri
Oncology Unit, Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy
Giovanni Vitale
Laboratory of Geriatric and Oncologic Neuroendocrinology Research, Istituto Auxologico Italiano, IRCCS, 20095 Cusano Milanino, Italy
Roberta Malaguarnera
Faculty of Medicine and Surgery, Kore University of Enna, 94100 Enna, Italy
Andrea Morrione
Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
Andrew H. Sims
MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland EH4 2XR, UK
Alfredo Ferro
Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, 95131 Catania, Italy
Marcello Maggiolini
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
Rosamaria Lappano
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy
Ernestina Marianna De Francesco
Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
Antonino Belfiore
Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
The insulin receptor isoform A (IR-A) plays an increasingly recognized role in fetal growth and tumor biology in response to circulating insulin and/or locally produced IGF2. This role seems not to be shared by the IR isoform B (IR-B). We aimed to dissect the specific impact of IR isoforms in modulating insulin signaling in triple negative breast cancer (TNBC) cells. We generated murine 4T1 TNBC cells deleted from the endogenous insulin receptor (INSR) gene and expressing comparable levels of either human IR-A or IR-B. We then measured IR isoform-specific in vitro and in vivo biological effects and transcriptome in response to insulin. Overall, the IR-A was more potent than the IR-B in mediating cell migration, invasion, and in vivo tumor growth. Transcriptome analysis showed that approximately 89% of insulin-stimulated transcripts depended solely on the expression of the specific isoform. Notably, in cells overexpressing IR-A, insulin strongly induced genes involved in tumor progression and immune evasion including chemokines and genes related to innate immunity. Conversely, in IR-B overexpressing cells, insulin predominantly induced the expression of genes primarily involved in the regulation of metabolic pathways and, to a lesser extent, tumor growth and angiogenesis.
