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Updated: Jan 27, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Modulation of Mitochondrial ERβ Expression Inhibits Triple-Negative Breast Cancer Tumor Progression by Activating
In-Sung Song1, Yu Jeong Jeong1, Seung Hun Jeong1
1Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
Background/Aims:
Breast cancer is a clinically and molecularly heterogeneous disease. Patients with triple-negative breast cancer (TNBC) have poorer outcomes than those with other breast cancer subtypes due to lack of effective molecular targets for therapy. The present study aimed to the identification of estrogen receptor (ER)β as a novel mitochondrial target in TNBC cells, together with underlying mechanisms.
Methods:
Expression of ERβ in clinical breast samples were examined by qRT-PCR, immunohistochemistry and immunoblotting. Subcellular distribution and binding of ERβ-Grp75 was determined by confocal microscopic analysis, co-immunoprecipitation experiments, and limited-detergent extraction of subcellular organelles. The effect of mitocondrial ERβ(mitoERβ) overexpression on cell proliferation and cell cycle distribution were assessed CCK-8 assays and FACS. Mitochondrial ROS, membrane potential, and Ca²⁺ level were measured using the specific fluorescent probes Mito-Sox, TMRE, and Rhod-2AM. The tumorigenic effect of mitoERβ overexpression was assessed using an anchorage-independent growth assay, sphere formation and a mouse orthotopic xenograft model.
Results:
ERβ expression was lower in tumor tissue than in adjacent normal tissue of patients with breast cancer, and low levels of mitochondrial ERβ (mitoERβ) also were associated with increased tumor recurrence after surgery. Overexpression of mitoERβ inhibited the proliferation of TNBC cells and tumor masses in an animal model. Moreover, overexpression of mitoERβ increased ATP production in TNBC cells and normal breast MCF10A cells, with the latter completely reversed by mitoERβ knockdown in MCF10A cells. Grp75 was found to positively regulate ERβ translocation into mitochondria via a direct interaction. Coimmunoprecipitation and subcellular fractionation experiments revealed that ERβ-Grp75 complex is stable in mitochondria.
Conclusion:
These results suggest that the up-regulation of mitoERβ in TNBC cells ensures proper mitochondrial transcription, activating the OXPHOS system to produce ATP. Studying the effects of mitoERβ on mitochondrial activity and specific mitochondrial gene expression in breast cancer might help predict tumor recurrence, inform clinical decision-making, and identify novel drug targets in the treatment of TNBC.
Insights
Estrogen receptor beta (ERβ) found in mitochondria may be a new target for triple-negative breast cancer (TNBC) treatment. Upregulating mitochondrial ERβ (mitoERβ) inhibits TNBC growth and enhances ATP production, offering potential therapeutic strategies.
Area of Science:
- Molecular biology
- Cancer research
- Mitochondrial biology
Background:
- Triple-negative breast cancer (TNBC) presents poorer outcomes due to limited targeted therapies.
- Estrogen receptor beta (ERβ) is explored as a novel mitochondrial target in TNBC.
Purpose of the Study:
- Identify ERβ as a mitochondrial target in TNBC cells.
- Elucidate the mechanisms underlying ERβ's role in TNBC.
Main Methods:
- Assessed ERβ expression in clinical breast samples (qRT-PCR, IHC, immunoblotting).
- Investigated ERβ-Grp75 interaction and mitochondrial translocation (confocal microscopy, co-IP).
- Evaluated effects of mitochondrial ERβ (mitoERβ) on cell proliferation, cell cycle, mitochondrial function, and tumorigenesis in vitro and in vivo.
Main Results:
- Lower ERβ expression in tumors correlated with increased recurrence.
- mitoERβ overexpression inhibited TNBC cell proliferation and tumor growth in mice.
- mitoERβ enhanced ATP production, linked to mitochondrial transcription and OXPHOS activation.
Conclusions:
- mitoERβ up-regulation in TNBC cells promotes mitochondrial transcription and OXPHOS, boosting ATP production.
- mitoERβ's role in mitochondrial activity may predict recurrence and identify new therapeutic targets for TNBC.
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