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Updated: Feb 15, 2026

Flow Cytometric Detection of Newly-formed Breast Cancer Stem Cell-like Cells After Apoptosis Reversal
Published on: January 26, 2019
Breast Cancer Targeting through Inhibition of the Endoplasmic Reticulum-Based Apoptosis Regulator Nrh/BCL2L10
Adrien Nougarede1, Nikolay Popgeorgiev1, Loay Kassem2
1Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon, France.
Abstract:
Drug resistance and metastatic relapse remain a top challenge in breast cancer treatment. In this study, we present preclinical evidence for a strategy to eradicate advanced breast cancers by targeting the BCL-2 homolog Nrh/BCL2L10, which we discovered to be overexpressed in >45% of a large cohort of breast invasive carcinomas. Nrh expression in these tumors correlated with reduced metastasis-free survival, and we determined it to be an independent marker of poor prognosis. Nrh protein localized to the endoplasmic reticulum. Mechanistic investigations showed that Nrh made BH4 domain-dependent interactions with the ligand-binding domain of the inositol-1,4,5-triphosphate receptor (IP3R), a type 1/3 Ca2+ channel, allowing Nrh to negatively regulate ER-Ca2+ release and to mediate antiapoptosis. Notably, disrupting Nrh/IP3R complexes by BH4 mimetic peptides was sufficient to inhibit the growth of breast cancer cells in vitro and in vivo Taken together, our results highlighted Nrh as a novel prognostic marker and a candidate therapeutic target for late stage breast cancers that may be addicted to Nrh.Significance: These findings offer a comprehensive molecular model for the activity of Nrh/BCL2L10, a little studied antiapoptotic molecule, prognostic marker, and candidate drug target in breast cancer. Cancer Res; 78(6); 1404-17. ©2018 AACR.
Insights
Targeting Nrh/BCL2L10, overexpressed in advanced breast cancers, offers a new strategy. Disrupting Nrh interactions with IP3R channels inhibits cancer cell growth, showing Nrh as a prognostic marker and therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Drug resistance and metastatic relapse are significant challenges in breast cancer treatment.
- BCL-2 homolog Nrh/BCL2L10 (Nrh) is overexpressed in over 45% of invasive breast carcinomas.
- Nrh overexpression correlates with reduced metastasis-free survival and is an independent poor prognostic marker.
Purpose of the Study:
- To investigate the role of Nrh/BCL2L10 in advanced breast cancer.
- To explore Nrh as a potential therapeutic target and prognostic marker.
- To elucidate the mechanism of Nrh's antiapoptotic activity.
Main Methods:
- Analysis of Nrh expression in a large cohort of breast invasive carcinomas.
- Immunohistochemistry to determine Nrh protein localization.
- Mechanistic studies involving interactions between Nrh and inositol-1,4,5-triphosphate receptor (IP3R).
- In vitro and in vivo experiments using BH4 mimetic peptides to disrupt Nrh/IP3R complexes.
Main Results:
- Nrh protein localizes to the endoplasmic reticulum.
- Nrh interacts with IP3R (a Ca2+ channel) in a BH4 domain-dependent manner.
- Nrh negatively regulates ER-Ca2+ release and mediates antiapoptosis.
- Disruption of Nrh/IP3R complexes inhibits breast cancer cell growth both in vitro and in vivo.
Conclusions:
- Nrh/BCL2L10 is a novel prognostic marker for breast cancer.
- Nrh is a potential therapeutic target for advanced breast cancers.
- Targeting Nrh/IP3R interactions offers a promising strategy for eradicating drug-resistant and metastatic breast cancers.
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