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Updated: Jan 20, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Contemplations on MDMX (MDM4) driving triple negative breast cancer circulating tumor cells and metastasis
Chong Gao1,2, Gu Xiao1, Jill Bargonetti1,2,3
1The Department of Biological Sciences at Hunter College, Belfer Building, City University of New York, New York, NY, USA.
Abstract:
MDMX (MDM4) is emerging as an important breast cancer (BC) biomarker, and oncoprotein, that can be targeted in combination with its well-known family member MDM2. While MDM2 has previously been implicated in driving BC metastasis, information about the role of MDMX in driving circulating tumor cells (CTCs) and BC metastasis is lacking. BCs often have alterations of MDM2, MDMX, and mutant p53 (mtp53). Therefore, the role of MDM2 and MDMX in the context of mtp53 in BCs requires further clarification. Our group has recently reported that triple negative breast cancer (TNBC) metastasis is dependent on both MDM2 and MDMX, and depleting MDM2 results in increased MDMX, but depleting MDMX does not cause an increase in MDM2. In the context of human TNBC expressing mtp53 in an orthotopic mouse model the down-regulation of MDMX virtually cleared CTCs from the blood. Contemplations, using the available literature, suggest that disrupting the stability and/or function of MDMX protein (and its downstream targets), in the context of mtp53 expressing BCs, might be beneficial for patient survival. It remains to be determined if blocking mtp53-MDMX pathways can inhibit early stage TNBC and eliminate CTCs that have the potential to form metastatic lesions.
Insights
Targeting MDMX (MDM4) protein in triple-negative breast cancer (TNBC) with mutant p53 significantly reduced circulating tumor cells (CTCs). This suggests MDMX is crucial for TNBC metastasis and a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- MDMX (MDM4) is an emerging breast cancer (BC) biomarker and oncoprotein, often co-occurring with MDM2 and mutant p53 (mtp53) in BCs.
- While MDM2's role in BC metastasis is known, MDMX's specific involvement in driving circulating tumor cells (CTCs) and metastasis remains unclear.
- Understanding the interplay between MDM2, MDMX, and mtp53 is crucial for clarifying their roles in BC progression.
Purpose of the Study:
- To investigate the role of MDMX in driving circulating tumor cells (CTCs) and metastasis in breast cancer (BC), particularly in the context of mutant p53 (mtp53).
- To explore the potential of targeting MDMX as a therapeutic strategy for inhibiting metastasis and improving survival in BC patients.
Main Methods:
- Utilized an orthotopic mouse model of human triple-negative breast cancer (TNBC) expressing mtp53.
- Assessed the effect of MDMX downregulation on the presence of CTCs in the blood.
- Analyzed the relationship between MDM2, MDMX, and mtp53 alterations in BC.
Main Results:
- Downregulation of MDMX in TNBC models expressing mtp53 led to a near-complete clearance of CTCs from circulation.
- Depleting MDM2 resulted in increased MDMX levels, whereas depleting MDMX did not increase MDM2 levels.
- TNBC metastasis was found to be dependent on both MDM2 and MDMX.
Conclusions:
- MDMX plays a critical role in driving CTCs and metastasis in mtp53-expressing TNBC.
- Targeting MDMX stability or function, especially in conjunction with mtp53, may represent a promising therapeutic approach for BC.
- Further research is needed to determine if blocking mtp53-MDMX pathways can inhibit early-stage TNBC and eliminate metastatic CTCs.
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