Ceramide-Induced Endoplasmic Reticulum Stress Reveals a Targetable Vulnerability in Endocrine Therapy-Resistant Breast Cancer

Authors

• Purab Pal
• Shweta Chitkara
• Godwin K Sarpey
• Aanshi Vashi
• Vipin Rawat
• Fatimah Alani
• Huiping Zhao
• Malik Ata
• Jun Qu
• Rachel Schiff
• Debra Tonetti
• Geoffrey L Greene
• Jonna Frasor
• Gunes Ekin Atilla-Gokcumen
• Jonathan L Coloff

Language

English

Publication Date

9-2-2026

Journal

Molecular Cancer Research

DOI

10.1158/1541-7786.MCR-25-0964

PMID

42233959

PMCID

PMC13375114

PubMedCentral® Posted Date

6-3-2026

PubMedCentral® Full Text Version

Post-print

Abstract

UNLABELLED: Despite the success of endocrine therapy (ET) in treating hormone receptor-positive breast cancer, a significant proportion of patients relapse during or after treatment, making ET resistance a major clinical challenge. Previously, we have shown that ET-resistant breast cancer cells exhibit reduced ceramide levels and an increased sensitivity to ceramide-induced cell death. In this study, we demonstrate that ceramides induce a distinct transcriptional reprogramming in ET-resistant cells, characterized by upregulation of endoplasmic reticulum stress (EnRS) pathways. Ceramide-induced EnRS is PERK-dependent and functionally linked to cell death in multiple models of ET resistance. Using a photoactivatable ceramide probe, we identify TRAM1 as a functionally important ceramide-interacting protein (CIP) in ET-resistant cells that correlates with worse relapse-free survival and a more aggressive breast cancer phenotype in patients with luminal breast cancer. Additionally, knockdown of TRAM1 phenocopies ceramide action in ET resistance, thereby suggesting its role in mediating ceramide-induced lethal actions in ET resistance. Together, our findings reveal that ET-resistant breast cancer cells are highly sensitive to PERK-mediated EnRS relative to ET-sensitive cells. Ceramides, likely via interactions with CIPs such as TRAM1, lead to PERK activation and consequential cell death in the ET-resistant breast cancer models. This sensitivity to ceramide-induced EnRS and cell death is a vulnerability that could be taken advantage of to treat ET-resistant breast cancer.

IMPLICATIONS: This study elucidates the functional relevance of ceramide depletion in ET-resistant breast cancer cells.

Keywords

Humans, Female, Ceramides, Breast Neoplasms, Drug Resistance, Neoplasm, Endoplasmic Reticulum Stress, Cell Line, Tumor, Animals, eIF-2 Kinase, Antineoplastic Agents, Hormonal, Mice

Published Open-Access

yes

Recommended Citation

Pal, Purab; Chitkara, Shweta; Sarpey, Godwin K; et al., "Ceramide-Induced Endoplasmic Reticulum Stress Reveals a Targetable Vulnerability in Endocrine Therapy-Resistant Breast Cancer" (2026). Faculty, Staff and Students Publications. 8254.
https://digitalcommons.library.tmc.edu/baylor_docs/8254