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Updated: Oct 16, 2025

Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
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Enhanced IFNα Signaling Promotes Ligand-Independent Activation of ERα to Promote Aromatase Inhibitor Resistance in

Taylor E Escher1, Prasad Dandawate1,2, Afreen Sayed1

  • 1Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.

Cancers
|October 23, 2021
PubMed

Insights

Interferon-alpha (IFNα) signaling activates estrogen receptor (ERα) in resistant breast cancer, promoting survival. Inhibiting IFNα reduces ERα activity and IFITM1 expression, offering a potential therapeutic strategy for aromatase inhibitor resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Aromatase inhibitors (AIs) are standard for estrogen receptor-positive (ER+) breast cancer but face resistance in ~30% of patients.
  • Upregulated interferon-alpha (IFNα) signaling is observed in AI-resistant breast cancers, driving survival gene IFITM1 expression.
  • The mechanism by which IFNα signaling mediates AI resistance remains unclear.

Purpose of the Study:

  • To elucidate the role of enhanced IFNα signaling in mediating resistance to AIs in ER+ breast cancer.
  • To investigate the interaction between IFNα signaling and estrogen receptor (ERα) activation in AI-resistant cells.

Main Methods:

  • Utilized MCF-7:5C cells, a model for AI-resistant breast cancer.
  • Investigated the interaction between STAT1 (IFNα signaling mediator) and ERα.
  • Assessed the impact of IFNα inhibition on ERα expression and ER-regulated genes.
  • Examined IFITM1 expression following ERα loss.
  • Performed chromatin immunoprecipitation to validate ERα and STAT1 binding to the IFITM1 promoter.

Main Results:

  • AI-resistant cells showed enhanced IFNα signaling and ligand-independent ERα activation.
  • STAT1 directly interacts with ERα.
  • Inhibition of IFNα signaling decreased ERα protein and ER-regulated gene expression.
  • Loss of ERα reduced IFITM1 expression, leading to cell death.
  • ERα and STAT1 were found to bind ERE sequences in the IFITM1 promoter.

Conclusions:

  • Hyperactivation of IFNα signaling promotes ligand-independent ERα activation in AI-resistant breast cancer.
  • This interaction drives both ER-regulated and interferon-stimulated gene expression, contributing to cell survival.
  • Targeting IFNα signaling may be a viable strategy to overcome AI resistance in ER+ breast cancer.
Keywords:
AI resistanceIFITM1STAT1aromatase inhibitorbreast cancerestrogen deprivationestrogen receptorinterferon alphainterferon-stimulated genes

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