Related Experiment Video
Updated: Sep 27, 2025
A Portal Vein Injection Model to Study Liver Metastasis of Breast Cancer
Published on: December 26, 2016
Reduction of Metastasis via Epigenetic Modulation in a Murine Model of Metastatic Triple Negative Breast Cancer
Jessica L S Zylla1,2, Mariah M Hoffman1,2, Simona Plesselova3
1Department of Biomedical Engineering, University of South Dakota, Sioux Falls, SD 57107, USA.
Abstract:
This study investigates the effects of a dual selective Class I histone deacetylase (HDAC)/lysine-specific histone demethylase 1A (LSD1) inhibitor known as 4SC-202 (Domatinostat) on tumor growth and metastasis in a highly metastatic murine model of Triple Negative Breast Cancer (TNBC). 4SC-202 is cytotoxic and cytostatic to the TNBC murine cell line 4T1 and the human TNBC cell line MDA-MB-231; the drug does not kill the normal breast epithelial cell line MCF10A. Furthermore, 4SC-202 reduces cancer cell migration. In vivo studies conducted in the syngeneic 4T1 model, which closely mimics human TNBC in terms of sites of metastasis, reveal reduced tumor burden and lung metastasis. The mechanism of action of 4SC-202 may involve effects on cancer stem cells (CSC) which can self-renew and form metastatic lesions. Approximately 5% of the total 4T1 cell population grown in three-dimensional scaffolds had a distinct CD44high/CD24low CSC profile which decreased after treatment. Bulk transcriptome (RNA) sequencing analyses of 4T1 tumors reveal changes in metastasis-related pathways in 4SC-202-treated tumors, including changes to expression levels of genes implicated in cell migration and cell motility. In summary, 4SC-202 treatment of tumors from a highly metastatic murine model of TNBC reduces metastasis and warrants further preclinical studies.
Insights
Domatinostat (4SC-202), a dual HDAC/LSD1 inhibitor, effectively reduced tumor growth and metastasis in a triple-negative breast cancer (TNBC) mouse model. This targeted therapy shows promise for treating aggressive TNBC by impacting cancer stem cells and metastasis pathways.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and a high propensity for metastasis.
- Targeting epigenetic regulators like histone deacetylases (HDACs) and lysine-specific histone demethylase 1A (LSD1) offers a potential therapeutic strategy.
Purpose of the Study:
- To investigate the anti-tumor and anti-metastatic effects of the dual HDAC/LSD1 inhibitor 4SC-202 (Domatinostat) in a highly metastatic murine model of TNBC.
- To explore the underlying mechanisms of 4SC-202 action, including its impact on cancer stem cells and metastasis-related gene expression.
Main Methods:
- In vitro assessment of 4SC-202 cytotoxicity, cytostatic effects, and migration inhibition on TNBC cell lines (4T1, MDA-MB-231) and a normal breast epithelial cell line (MCF10A).
- In vivo efficacy studies using a syngeneic 4T1 TNBC murine model to evaluate tumor burden and lung metastasis.
- Analysis of cancer stem cell (CSC) populations (CD44high/CD24low) and bulk transcriptome sequencing (RNA-seq) of treated tumors.
Main Results:
- 4SC-202 demonstrated selective cytotoxicity and cytostatic effects against TNBC cell lines, with no significant impact on normal breast epithelial cells.
- In vivo studies showed a significant reduction in tumor burden and lung metastasis in 4SC-202 treated mice.
- Treatment with 4SC-202 led to a decrease in the CD44high/CD24low CSC population and altered expression of metastasis-related genes involved in cell migration and motility.
Conclusions:
- 4SC-202 exhibits potent anti-tumor and anti-metastatic activity in a preclinical TNBC model.
- The drug's mechanism may involve targeting cancer stem cells and modulating key metastasis pathways.
- 4SC-202 warrants further investigation as a potential therapeutic agent for metastatic TNBC.
