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

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

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. marcello.maggiolini@unical.it.
  • 7 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036, Rende, Italy. rosamaria.lappano@unical.it.
  • # 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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