Thyroid Hormone Receptor ß Inhibits Self-Renewal Capacity of Breast Cancer Stem Cells.

ABSTRACT

Background: A subpopulation of cancer stem cells (CSCs) with capacity for self-renewal is believed to drive initiation, progression, and relapse of breast tumors. Methods: Since the thyroid hormone receptor ß (TRß) appears to suppress breast tumor growth and metastasis, we have analyzed the possibility that TRß could affect the CSC population using MCF-7 cells grown under adherent conditions or as mammospheres, as well as inoculation into immunodeficient mice. Results: Treatment of TRß-expressing MCF-7 cells (MCF7-TRß cells) with the thyroid hormone triiodothyronine (T3) decreased significantly CD44+/CD24- and ALDH+ cell subpopulations, the efficiency of mammosphere formation, the self-renewal capacity of CSCs in limiting dilution assays, the expression of the pluripotency factors in the mammospheres, and tumor initiating capacity in immunodeficient mice, indicating that the hormone reduces the CSC population present within the bulk MCF7-TRß cultures. T3 also decreased migration and invasion, a hallmark of CSCs. Transcriptome analysis showed downregulation of the estrogen receptor alpha (ERα) and ER-responsive genes by T3. Furthermore, among the T3-repressed genes, there was an enrichment in genes containing binding sites for transcription factors that are key determinants of luminal-type breast cancers and are required for ER binding to chromatin. Conclusion: We demonstrate a novel role of TRß in the biology of CSCs that may be related to its action as a tumor suppressor in breast cancer.