Interleukin-1β mediates a tumor-supporting environment prompted by IGF1 in triple-negative breast cancer (TNBC)

  • J Transl Med. 2025 Jun 17;23(1):660. doi: 10.1186/s12967-025-06730-w.
Domenica Scordamaglia  #  1 ,  Marianna Talia  #  1 ,  Francesca Cirillo  2 ,  Azzurra Zicarelli  2 ,  Adelina Assunta Mondino  1 ,  Salvatore De Rosis  1 ,  Marika Di Dio  1 ,  Francesca Silvestri  1 ,  Chiara Meliti  1 ,  Anna Maria Miglietta  3 ,  Carlo Capalbo  1  4 ,  Ernestina Marianna De Francesco  2 ,  Antonino Belfiore  5 ,  Marcello Maggiolini  6 ,  Rosamaria Lappano  7
Affiliations
  • 1. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy.
  • 2. Department of Medicine and Surgery, University of Enna "Kore", 94100, Enna, Italy.
  • 3. Breast and General Surgery Unit, Annunziata Hospital Cosenza, 87100, Cosenza, Italy.
  • 4. Complex Operative Oncology Unit, Annunziata Hospital Cosenza, 87100, Cosenza, Italy.
  • 5. Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122, Catania, Italy.
  • 6. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy. [email protected].
  • 7. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy. [email protected].
  • # Contributed equally.
PMID: 40528195 DOI: 10.1186/s12967-025-06730-w
Abstract

Background: The intricate mechanisms that associate obesity with triple-negative breast Cancer (TNBC) remain to be disclosed. Considering that obesity is linked with an increased bioavailability of the insulin-like growth factor 1 (IGF1), we evaluated whether IGF1 triggers aggressive features in TNBC cells and the molecular paths involved.

Methods: Gene expression and Chromatin Immunoprecipitation experiments, ELISA, immunoblotting, immunoprecipitation and immunofluorescence assays, combined with two-dimensional and three-dimensional in vitro model-based studies, were used to investigate the molecular mechanisms through which IGF1 may promote proliferative and motile responses in TNBC cells and reprogram normal fibroblasts into cancer-associated fibroblasts (CAFs)-like cells. The translational relevance of the results obtained was supported by bioinformatics analyses leveraging data from extensive TNBC patient databases.

Results: We found that the cytokine interleukin-1β (IL-1β) mediates certain IGF1 actions within the tumor microenvironment, hence facilitating the TNBC landscape. Mechanistically, we assessed that the IGF1/IGF1 receptor (IGFIR) axis induces the Collagen VI-dependent activation of Discoidin Domain Receptor 1 (DDR1) and the subsequent increase of the G protein Estrogen receptor (GPER), toward IL-1β regulation and secretion. Consequently, IL-1β promoted both the autocrine stimulation of TNBC cells and the differentiation of normal fibroblasts into cancer-associated fibroblasts (CAFs)-like cells, which in turn achieved a proliferative profile and enhanced the motility of TNBC cells.

Conclusions: IL-1β may be considered as a therapeutic target in more comprehensive approaches in obese TNBC patients exhibiting high IGF-1 bioavailability.

Keywords
Cancer associated fibroblasts (CAFs); Discoidin domain receptor 1 (DDR1); G protein estrogen receptor (GPER); Insulin-like growth factor 1 (IGF1); Interleukin 1β (IL1β); Triple-negative breast cancer (TNBC).
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