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Updated: Dec 14, 2025
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Identification of BBOX1 as a Therapeutic Target in Triple-Negative Breast Cancer
Chengheng Liao1, Yang Zhang2, Cheng Fan3
1Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas.
Abstract:
Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease. Because of its heterogeneity and lack of hormone receptors or HER2 expression, targeted therapy is limited. Here, by performing a functional siRNA screening for 2-OG-dependent enzymes, we identified gamma-butyrobetaine hydroxylase 1 (BBOX1) as an essential gene for TNBC tumorigenesis. BBOX1 depletion inhibits TNBC cell growth while not affecting normal breast cells. Mechanistically, BBOX1 binds with the calcium channel inositol-1,4,5-trisphosphate receptor type 3 (IP3R3) in an enzymatic-dependent manner and prevents its ubiquitination and proteasomal degradation. BBOX1 depletion suppresses IP3R3-mediated endoplasmic reticulum calcium release, therefore impairing calcium-dependent energy-generating processes including mitochondrial respiration and mTORC1-mediated glycolysis, which leads to apoptosis and impaired cell-cycle progression in TNBC cells. Therapeutically, genetic depletion or pharmacologic inhibition of BBOX1 inhibits TNBC tumor growth in vitro and in vivo. Our study highlights the importance of targeting the previously uncharacterized BBOX1-IP3R3-calcium oncogenic signaling axis in TNBC. SIGNIFICANCE: We provide evidence from unbiased screens that BBOX1 is a potential therapeutic target in TNBC and that genetic knockdown or pharmacologic inhibition of BBOX1 leads to decreased TNBC cell fitness. This study lays the foundation for developing effective BBOX1 inhibitors for treatment of this lethal disease.This article is highlighted in the In This Issue feature, p. 1611.
Insights
Gamma-butyrobetaine hydroxylase 1 (BBOX1) is essential for triple-negative breast cancer (TNBC) growth. Inhibiting BBOX1 stops TNBC tumor progression by disrupting calcium signaling, offering a new therapeutic strategy.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Triple-negative breast cancer (TNBC) is aggressive with limited targeted therapy options due to its heterogeneity and lack of specific biomarkers.
- The need for novel therapeutic targets in TNBC is critical due to its high lethality and poor prognosis.
Purpose of the Study:
- To identify essential genes and potential therapeutic targets for triple-negative breast cancer (TNBC) through functional screening.
- To elucidate the mechanism by which gamma-butyrobetaine hydroxylase 1 (BBOX1) contributes to TNBC tumorigenesis.
- To evaluate the therapeutic potential of targeting BBOX1 in TNBC.
Main Methods:
- Functional siRNA screening of 2-OG-dependent enzymes to identify essential genes in TNBC.
- Investigated the interaction between BBOX1 and inositol-1,4,5-trisphosphate receptor type 3 (IP3R3) and its effect on calcium signaling.
- Assessed the impact of BBOX1 depletion or inhibition on TNBC cell growth, apoptosis, cell-cycle progression, mitochondrial respiration, and glycolysis in vitro and in vivo.
Main Results:
- Gamma-butyrobetaine hydroxylase 1 (BBOX1) was identified as essential for TNBC cell growth but not for normal breast cells.
- BBOX1 interacts with IP3R3, preventing its ubiquitination and degradation, thereby maintaining calcium release and supporting energy metabolism.
- BBOX1 depletion or inhibition suppressed TNBC tumor growth by impairing calcium-dependent processes, leading to apoptosis and cell-cycle arrest.
Conclusions:
- BBOX1 is a critical oncogenic driver in TNBC, functioning through the BBOX1-IP3R3-calcium signaling axis.
- Targeting BBOX1, via genetic or pharmacologic inhibition, demonstrates significant therapeutic potential for TNBC.
- This study establishes BBOX1 as a promising novel therapeutic target for treating aggressive triple-negative breast cancer.
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