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Updated: Jun 4, 2026

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Ceramide-Induced Endoplasmic Reticulum Stress Reveals a Targetable Vulnerability in Endocrine Therapy-Resistant
Purab Pal1, Shweta Chitkara2, Godwin K Sarpey1
1Department of Physiology and Biophysics, University of Illinois Chicago, Chicago, Illinois.
Abstract:
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.
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