Related Experiment Video
Updated: Apr 16, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Methionine Deprivation Induces a Targetable Vulnerability in Triple-Negative Breast Cancer Cells by Enhancing TRAIL
Elena Strekalova1, Dmitry Malin1, David M Good1
1Department of Medicine, University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
Purpose:
Many neoplasms are vulnerable to methionine deficiency by mechanisms that are poorly understood. Because gene profiling studies have revealed that methionine depletion increases TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) mRNA, we postulated that methionine stress sensitizes breast cancer cells to proapoptotic TRAIL-R2 agonists.
Experimental Design:
Human triple (ER/PR/HER2)-negative breast carcinoma cell lines were cultured in control or methionine-free media. The effects of methionine depletion on TRAIL receptor expression and sensitivity to chemotherapy or a humanized agonistic TRAIL-R2 monoclonal antibody (lexatumumab) were determined. The melanoma-associated antigen MAGED2 was silenced to delineate its functional role in sensitizing TNBC cells to methionine stress. An orthotopic TNBC model was utilized to evaluate the effects of dietary methionine deficiency, lexatumumab, or the combination.
Results:
Methionine depletion sensitized TNBC cells to lexatumumab-induced caspase activation and apoptosis by increasing TRAIL-R2 mRNA and cell surface expression. MCF-10A cells transformed by oncogenic H-Ras, but not untransformed cells, and matrix-detached TNBC cells were highly sensitive to the combination of lexatumumab and methionine depletion. Proteomics analyses revealed that MAGED2, which has been reported to reduce TRAIL-R2 expression, was suppressed by methionine stress. Silencing MAGED2 recapitulated features of methionine deprivation, including enhanced mRNA and cell surface expression of TRAIL receptors and increased sensitivity to TRAIL receptor agonists. Dietary methionine deprivation enhanced the antitumor effects of lexatumumab in an orthotopic metastatic TNBC model.
Conclusions:
Methionine depletion exposes a targetable defect in TNBC cells by increasing TRAIL-R2 expression. Our findings provide the foundation for a clinical trial combining dietary methionine restriction and TRAIL-R2 agonists. Clin Cancer Res; 21(12); 2780-91. ©2015 AACR.
Insights
Methionine restriction sensitizes triple-negative breast cancer (TNBC) cells to TRAIL-R2 agonists by increasing receptor expression. This suggests combining dietary methionine restriction with TRAIL-R2 agonists for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Neoplasms exhibit vulnerability to methionine deficiency through poorly understood mechanisms.
- Gene profiling indicates methionine depletion elevates TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) mRNA expression.
Purpose of the Study:
- To investigate if methionine stress sensitizes breast cancer cells to proapoptotic TRAIL-R2 agonists.
- To explore the role of MAGED2 in sensitizing triple-negative breast cancer (TNBC) cells to methionine stress.
Main Methods:
- Cultured human triple-negative breast carcinoma cell lines in control or methionine-free media.
- Assessed effects of methionine depletion on TRAIL receptor expression and sensitivity to lexatumumab (TRAIL-R2 agonist) and chemotherapy.
- Utilized an orthotopic TNBC model to evaluate dietary methionine deficiency and lexatumumab combination therapy.
- Silenced melanoma-associated antigen MAGED2 to determine its role in methionine stress sensitization.
Main Results:
- Methionine depletion increased TRAIL-R2 mRNA and cell surface expression, sensitizing TNBC cells to lexatumumab-induced apoptosis.
- Transformed MCF-10A cells and matrix-detached TNBC cells showed high sensitivity to combined lexatumumab and methionine depletion.
- Methionine stress suppressed MAGED2, which normally reduces TRAIL-R2 expression, mimicking methionine deprivation effects.
- Dietary methionine deprivation enhanced lexatumumab's antitumor effects in an orthotopic metastatic TNBC model.
Conclusions:
- Methionine depletion reveals a targetable defect in TNBC cells by upregulating TRAIL-R2 expression.
- Findings support a clinical trial combining dietary methionine restriction with TRAIL-R2 agonists for TNBC treatment.
