Reduction of Metastasis via Epigenetic Modulation in a Murine Model of Metastatic Triple Negative Breast Cancer (TNBC)

Jessica L S Zylla; Mariah M Hoffman; Simona Plesselova; Somshuvra Bhattacharya; Kristin Calar; Yohannes Afeworki; Pilar de la Puente; Etienne Z Gnimpieba; W Keith Miskimins; Shanta M Messerli

doi:10.3390/cancers14071753

Reduction of Metastasis via Epigenetic Modulation in a Murine Model of Metastatic Triple Negative Breast Cancer (TNBC)

Cancers (Basel). 2022 Mar 30;14(7):1753. doi: 10.3390/cancers14071753.

Authors

Jessica L S Zylla^{1

2}, Mariah M Hoffman^{1

2}, Simona Plesselova³, Somshuvra Bhattacharya³, Kristin Calar³, Yohannes Afeworki⁴, Pilar de la Puente^{3

5

6}, Etienne Z Gnimpieba^{1

2}, W Keith Miskimins^{3

6}, Shanta M Messerli^{1

2

3

7}

Affiliations

¹ Department of Biomedical Engineering, University of South Dakota, Sioux Falls, SD 57107, USA.
² 2-Dimensional Materials for Biofilm Engineering Science and Technology (2DBEST) Center, Sioux Falls, SD 57107, USA.
³ Cancer Biology & Immunotherapies, Sanford Research, Sioux Falls, SD 57104, USA.
⁴ Functional Genomics and Bioinformatics Core, Sanford Research, Sioux Falls, SD 57104, USA.
⁵ Department of Surgery, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57105, USA.
⁶ Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD 57006, USA.
⁷ Department of Biology and Microbiology, South Dakota State University, Brookings, SD 57006, 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 CD44^high/CD24^low 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.

Keywords: 4SC-202; TNBC; cancer stem cells; metastasis.

Abstract

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