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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>IL-1β may be considered as a therapeutic target in more comprehensive approaches in obese TNBC patients exhibiting high IGF-1 bioavailability.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月17日

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  • Domenica Scordamaglia,
  • Marianna Talia,
  • Francesca Cirillo,
  • Azzurra Zicarelli,
  • Adelina Assunta Mondino,
  • Salvatore De Rosis,
  • Marika Di Dio,
  • Francesca Silvestri,
  • Chiara Meliti,
  • Anna Maria Miglietta,
  • Carlo Capalbo,
  • Ernestina Marianna De Francesco,
  • Antonino Belfiore,
  • Marcello Maggiolini,
  • Rosamaria Lappano

摘要

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.