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Updated: Jun 1, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Enhanced metastasis suppression by targeting TRAIL receptor 2 in a murine model of triple-negative breast cancer
Dmitry Malin1, Feng Chen, Carol Schiller
1Cell Death Regulation Laboratory, Department of Medicine, and Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Purpose:
Metastatic breast cancer is a deadly disease which requires new therapeutic strategies. Endogenous TNF-related apoptosis-inducing ligand (TRAIL) functions as a metastasis suppressor by activating proapoptotic TRAIL receptors (TRAIL-R1/DR4 and/or TRAIL-R2/DR5) in transformed cells, making it an attractive pathway for antimetastatic therapies. However, it is unclear whether TRAIL-R1 or TRAIL-R2 is a better therapeutic target in metastatic breast cancer.
Experimental Design:
Several metastatic, triple (estrogen receptor, progesterone receptor, and HER2)-negative cancer cell lines were treated with human agonistic monoclonal antibodies targeting TRAIL-R1 (mapatumumab) or TRAIL-R2 (lexatumumab). The effects on cell viability, apoptosis, and caspase-8 activation were determined. An orthotopic model of triple-negative breast cancer in which fluorescently labeled breast cancer cells metastasize from the mammary gland to lymph nodes and lung was utilized to evaluate the effects of mapatumumab, lexatumumab, or doxorubicin on primary and metastatic tumor burden in vivo.
Results:
Lexatumumab was more effective than mapatumumab in activating caspase-8, inducing apoptosis and inhibiting long-term survival of metastatic cancer cells, which expressed both TRAIL-R1 and TRAIL-R2. Human mammary epithelial cells transformed by oncogenic Ras were more sensitive to lexatumumab than nontransformed cells. Lexatumumab inhibited lymph node and lung metastases more robustly than mapatumumab in an orthotopic model of triple-negative breast cancer; both agents inhibited mammary tumor growth. In addition, lexatumumab was more effective than doxorubicin at suppressing metastases at doses of doxorubicin that were associated with toxicity, even though doxorubicin reduced primary tumor burden more robustly than lexatumumab.
Conclusion:
Targeting TRAIL-R2 receptor may be an effective therapeutic strategy for metastatic breast cancer.
Insights
Targeting the TRAIL-R2 receptor with lexatumumab shows promise for treating metastatic breast cancer. This antibody effectively suppressed cancer cell survival and metastasis in preclinical models, outperforming TRAIL-R1 targeting.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Metastatic breast cancer necessitates novel therapeutic strategies.
- Endogenous TNF-related apoptosis-inducing ligand (TRAIL) acts as a metastasis suppressor by activating TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5).
- The comparative efficacy of targeting TRAIL-R1 versus TRAIL-R2 in metastatic breast cancer remains unclear.
Purpose of the Study:
- To determine whether TRAIL-R1 or TRAIL-R2 is a more effective therapeutic target in metastatic breast cancer.
- To evaluate the efficacy of antibodies targeting TRAIL-R1 (mapatumumab) and TRAIL-R2 (lexatumumab) in preclinical models of metastatic breast cancer.
Main Methods:
- Treatment of metastatic, triple-negative breast cancer cell lines with mapatumumab or lexatumumab.
- Assessment of cell viability, apoptosis, and caspase-8 activation.
- In vivo evaluation in an orthotopic triple-negative breast cancer model using mapatumumab, lexatumumab, or doxorubicin to assess primary and metastatic tumor burden.
Main Results:
- Lexatumumab demonstrated superior efficacy over mapatumumab in activating caspase-8, inducing apoptosis, and inhibiting long-term survival of metastatic cancer cells.
- Lexatumumab more effectively inhibited lymph node and lung metastases in vivo compared to mapatumumab.
- Lexatumumab showed greater efficacy in suppressing metastases than doxorubicin at non-toxic doses, despite doxorubicin's more robust reduction of primary tumor burden.
Conclusions:
- Targeting the TRAIL-R2 receptor represents a potentially effective therapeutic strategy for metastatic breast cancer.
- Lexatumumab, an anti-TRAIL-R2 antibody, exhibits significant antimetastatic activity in preclinical models.
- TRAIL-R2 is a promising therapeutic target for overcoming metastatic breast cancer progression.
