Related Experiment Video
Updated: Jul 21, 2025
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
Targeted Destruction of S100A4 Inhibits Metastasis of Triple Negative Breast Cancer Cells
Thamir M Ismail1, Rachel G Crick2, Min Du3
1Department of Biochemistry and Systems Biology, University of Liverpool, Liverpool L69 7ZB, UK.
Abstract:
Most patients who die of cancer do so from its metastasis to other organs. The calcium-binding protein S100A4 can induce cell migration/invasion and metastasis in experimental animals and is overexpressed in most human metastatic cancers. Here, we report that a novel inhibitor of S100A4 can specifically block its increase in cell migration in rat (IC50, 46 µM) and human (56 µM) triple negative breast cancer (TNBC) cells without affecting Western-blotted levels of S100A4. The moderately-weak S100A4-inhibitory compound, US-10113 has been chemically attached to thalidomide to stimulate the proteasomal machinery of a cell. This proteolysis targeting chimera (PROTAC) RGC specifically eliminates S100A4 in the rat (IC50, 8 nM) and human TNBC (IC50, 3.2 nM) cell lines with a near 20,000-fold increase in efficiency over US-10113 at inhibiting cell migration (IC50, 1.6 nM and 3.5 nM, respectively). Knockdown of S100A4 in human TNBC cells abolishes this effect. When PROTAC RGC is injected with mouse TNBC cells into syngeneic Balb/c mice, the incidence of experimental lung metastases or local primary tumour invasion and spontaneous lung metastasis is reduced in the 10-100 nM concentration range (Fisher's Exact test, p ≤ 0.024). In conclusion, we have established proof of principle that destructive targeting of S100A4 provides the first realistic chemotherapeutic approach to selectively inhibiting metastasis.
Insights
Researchers developed a novel PROTAC RGC that degrades the S100A4 protein, effectively inhibiting cancer metastasis in cell lines and animal models. This offers a new therapeutic strategy for metastatic cancers.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Cancer metastasis is a primary cause of cancer-related deaths.
- S100A4 protein promotes cell migration, invasion, and metastasis in various cancers.
- S100A4 is overexpressed in most human metastatic cancers, making it a potential therapeutic target.
Purpose of the Study:
- To investigate the efficacy of a novel S100A4 inhibitor and a proteolysis targeting chimera (PROTAC) in blocking cancer cell migration and metastasis.
- To establish proof of principle for targeting S100A4 for the development of anti-metastasis therapies.
Main Methods:
- Developed a PROTAC (RGC) by linking a weak S100A4 inhibitor (US-10113) to thalidomide to induce S100A4 degradation via proteasomal machinery.
- Assessed the inhibitory effects of US-10113 and PROTAC RGC on cell migration in rat and human triple-negative breast cancer (TNBC) cell lines.
- Evaluated the anti-metastatic efficacy of PROTAC RGC in a mouse model of TNBC.
Main Results:
- PROTAC RGC specifically eliminated S100A4 in rat and human TNBC cells with significantly higher efficiency (IC50, 3.2-8 nM) compared to the inhibitor alone (IC50, 46-56 µM).
- PROTAC RGC demonstrated a ~20,000-fold increase in efficiency at inhibiting cell migration (IC50, 1.6-3.5 nM).
- PROTAC RGC significantly reduced lung metastasis and primary tumor invasion in a mouse model at concentrations of 10-100 nM.
Conclusions:
- Destructive targeting of S100A4 using PROTAC RGC is a highly effective strategy for inhibiting cancer metastasis.
- This approach represents the first realistic chemotherapeutic strategy for selectively inhibiting metastasis.
- Further development of S100A4-targeting PROTACs holds promise for treating metastatic cancers.
