Steroid receptor coactivator-3 as a target for anaplastic thyroid cancer

in Endocrine-Related Cancer
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  • 1 Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  • 2 Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
  • 3 Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina
  • 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

Correspondence should be addressed to S Cheng: chengs@mail.nih.gov
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Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy without effective therapeutic options to improve survival. Steroid receptor coactivator-3 (SRC-3) is a transcriptional coactivator whose amplification and/or overexpression has been identified in many cancers. In this study, we explored the expression of SRC-3 in ATCs and the effects of a new class of SRC-3 inhibitor-2 (SI-2) in human ATC cells (THJ-11T and THJ-16T cells) and mouse xenograft models to assess therapeutic potential of SI-2 for the treatment of ATC. SRC-3 protein abundance was significantly higher in human ATC tissue samples and ATC cells than in differentiated thyroid carcinomas or normal controls. SI-2 treatment effectively reduced the SRC-3 expression in both ATC cells and ATC xenograft tumors induced by these cells. Cancer cell survival in ATC cells and tumor growth in xenograft tumors were significantly reduced by SI-2 treatment through induction of cancer cell apoptosis and cell cycle arrest. SI-2 also reduced cancer stem-like cells as shown by an inhibition of tumorsphere formation, ALDH activity, and expression of stem cell markers in ATC. These findings indicate that SRC-3 is a potential therapeutic target for treatment of ATC patients and that SI-2 is a potent and promising candidate for a new therapeutic agent.

Supplementary Materials

    • Table S1. Kegg Gene Sets Enriched in Tumors with Top 30 NCOA3 Expression Analyzed by Gene Set Enrichment Analysis in TCGA-THCA (versus Tumors with Bottom 30 NCOA3 Expression).
    • Table S2. Hallmark Gene Sets Enriched in Tumors with Top 30 NCOA3 Expression Analyzed by Gene Set Enrichment Analysis in TCGA-THCA (versus Tumors with Bottom 30 NCOA3 Expression).
    • Table S3. GSEA Results for Kegg or Hallmark Gene Sets in Tumors with Bottom 30 NCOA3 Expression in TCGA-THCA (versus Tumors with Top 30 NCOA3 Expression).
    • Reference Table I. Kegg or Hallmark Gene Sets Enriched in Tumors with Top Quartile NCOA3 Expression Analyzed by Gene Set Enrichment Analysis in TCGA-THCA (versus Tumors with Low Quartile NCOA3 Expression; n = 125, respectively).
    • Supplementary Fig. 1
    • Supplementary Fig. 2

 

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