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Ceramide-induced Endoplasmic Reticulum Stress as a Targetable Vulnerability in Endocrine Therapy-Resistant Breast

Purab Pal1, Shweta Chitkara2, Godwin K Sarpey1

  • 1Department of Physiology and Biophysics, University of Illinois Chicago, IL, USA.

Biorxiv : the Preprint Server for Biology
|September 2, 2025
PubMed
Summary
This summary is machine-generated.

Endocrine therapy resistance in breast cancer involves reduced ceramides and increased sensitivity to ceramide-induced cell death. Ceramides activate endoplasmic reticulum stress (EnRS) pathways via PERK, leading to cell death in resistant cells, particularly through TRAM1 interaction.

Keywords:
CeramideCeramide-interacting proteinsEndocrine therapy resistanceEndoplasmic reticulum stressLuminal breast cancerPERKTRAM1

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Endocrine therapy (ET) is effective for hormone receptor-positive breast cancer but faces challenges with treatment resistance and patient relapse.
  • ET-resistant breast cancer cells exhibit altered ceramide metabolism, showing reduced levels and increased sensitivity to ceramide-induced cell death.

Purpose of the Study:

  • To investigate the mechanisms by which ceramides induce cell death in ET-resistant breast cancer cells.
  • To identify specific proteins involved in ceramide-mediated cell death pathways in ET resistance.

Main Methods:

  • Analysis of transcriptional reprogramming in ET-resistant cells upon ceramide treatment.
  • Assessment of the role of endoplasmic reticulum stress (EnRS) and the PERK pathway in ceramide-induced cell death.
  • Utilizing a photoactivatable ceramide probe to identify ceramide-interacting proteins (CIPs).
  • Investigating the function of TRAM1 in ET resistance models and patient data.

Main Results:

  • Ceramides induce a distinct transcriptional reprogramming in ET-resistant cells, upregulating EnRS pathways.
  • Ceramide-induced EnRS is dependent on the PERK pathway and mediates cell death in multiple ET resistance models.
  • TRAM1 was identified as a key ceramide-interacting protein (CIP) in ET-resistant cells, associated with poorer relapse-free survival and aggressive breast cancer phenotypes.
  • Knockdown of TRAM1 mimicked the effects of ceramide in ET resistance, highlighting its role in ceramide-induced cell death.

Conclusions:

  • ET-resistant breast cancer cells are more sensitive to PERK-mediated EnRS compared to ET-sensitive cells.
  • Ceramides exploit this sensitivity by interacting with CIPs like TRAM1, activating PERK and inducing cell death preferentially in ET-resistant models.
  • Targeting the ceramide-TRAM1-PERK axis presents a potential therapeutic strategy for overcoming ET resistance in breast cancer.