Novel Mechanisms of Tumor Promotion by the Insulin Receptor Isoform A in Triple-Negative Breast Cancer Cells
Creators
- Vella Veronica1
- Giuliano Marika1
- La Ferlita Alessandro2
- Pellegrino Michele3
- Gaudenzi Germano4
- Alaimo Salvatore5
- Massimino Michele6
- Pulvirenti Alfredo5
- Dicitore Alessandra4
- Vigneri Paolo6
- Vitale Giovanni4
- Malguarnera Roberta7
- Morrione Andrea8
- Sims Andrew H9
- Ferro Alfredo2
- Maggiolini Marcello3
- Lappano Rosamaria3
- De Francesco Ernestina Marianna10
- Belfiore Antonino10
- 1. Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy
- 2. Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, 95131 Catania, Italy.
- 3. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy.
- 4. Laboratory of Geriatric and Oncologic Neuroendocrinology Research, Istituto Auxologico Italiano, IRCCS, 20095 Cusano Milanino, Italy.
- 5. Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, 95131 Catania, Italy
- 6. Oncology Unit, Department of Clinical and Experimental Medicine, University of Catania, 95124 Catania, Italy.
- 7. Faculty of Medicine and Surgery, Kore University of Enna, 94100 Enna, Italy
- 8. 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.
- 9. MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland EH4 2XR, UK.
- 10. Endocrinology Unit, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy.
Description
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.
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