RAGE inhibition blunts insulin-induced oncogenic signals in breast cancer

Breast Cancer Research

Research

A. Pulvirenti¹  S. Pettinato²  D. C. Rigiracciolo³  D. Scordamaglia⁴  M. Maggiolini⁴  M. Talia⁴  F. Cirillo⁴  R. Lappano⁴  M. Pellegrino⁴  E. M. De Francesco⁵  V. Sergi⁵  V. Rapicavoli⁵  A. Belfiore⁵  G. Scavo⁵  V. Vella⁵  M. G. Muoio⁶  M. G. Galasso⁷ 

[1] Bioinformatics Unit, Department of Clinical and Experimental Medicine, University of Catania, 95131, Catania, Italy;Breast Unit Breast Surgery, Garibaldi-Nesima Hospital, 95122, Catania, Italy;Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Via Adamello 16, 20139, Milan, Italy;Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy;Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122, Catania, Italy;Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, 95122, Catania, Italy;Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy;Pathological Anatomy Unit, Garibaldi-Nesima Hospital, 95122, Catania, Italy;

关键词: Insulin;    Insulin receptor;    Breast cancer;    RAGE;    CAFs;   

DOI  :  10.1186/s13058-023-01686-5

 received in 2023-03-20, accepted in 2023-07-11,  发布年份 2023

来源: Springer

【 摘 要 】

The receptor for advanced glycation end products (RAGE) is implicated in diabetes and obesity complications, as well as in breast cancer (BC). Herein, we evaluated whether RAGE contributes to the oncogenic actions of Insulin, which plays a key role in BC progression particularly in obese and diabetic patients. Analysis of the publicly available METABRIC study, which collects gene expression and clinical data from a large cohort (n = 1904) of BC patients, revealed that RAGE and the Insulin Receptor (IR) are co-expressed and associated with negative prognostic parameters. In MCF-7, ZR75 and 4T1 BC cells, as well as in patient-derived Cancer-Associated Fibroblasts, the pharmacological inhibition of RAGE as well as its genetic depletion interfered with Insulin-induced activation of the oncogenic pathway IR/IRS1/AKT/CD1. Mechanistically, IR and RAGE directly interacted upon Insulin stimulation, as shown by in situ proximity ligation assays and coimmunoprecipitation studies. Of note, RAGE inhibition halted the activation of both IR and insulin like growth factor 1 receptor (IGF-1R), as demonstrated in MCF-7 cells KO for the IR and the IGF-1R gene via CRISPR-cas9 technology. An unbiased label-free proteomic analysis uncovered proteins and predicted pathways affected by RAGE inhibition in Insulin-stimulated BC cells. Biologically, RAGE inhibition reduced cell proliferation, migration, and patient-derived mammosphere formation triggered by Insulin. In vivo, the pharmacological inhibition of RAGE halted Insulin-induced tumor growth, without affecting blood glucose homeostasis. Together, our findings suggest that targeting RAGE may represent an appealing opportunity to blunt Insulin-induced oncogenic signaling in BC.

【 授权许可】

CC BY   
© The Author(s) 2023

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