Thyroid Hormone Receptor β 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 b (TRb) appears to suppress breast tumor growth and metastasis, we have analyzed the possibility that TRb 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 TRb-expressing MCF-7 cells (MCF7-TRb cells) with the thyroid hormone triiodothyronine (T3) decreased significantly CD44 + /CD24and 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-TRb cultures. T3 also decreased migration and invasion, a hallmark of CSCs. Transcriptome analysis showed downregulation of the estrogen receptor alpha (ERa) 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 luminaltype breast cancers and are required for ER binding to chromatin. Conclusion: We demonstrate a novel role of TRb in the biology of CSCs that may be related to its action as a tumor suppressor in breast cancer.

Cytoplasmic and Nuclear Forms of Thyroid Hormone Receptor β1 Are Inversely Associated with Survival in Primary Breast Cancer

“…Considering the subcellular THRβ1 localization seems to be essential for further analysis of its impact on patient outcome. A recent in vitro study suggested a novel role of THRβ, namely THRβ1, in the biology of cancer stem cells that could explain its action as a tumor suppressor in BC [38]. In our study, both nuclear and cytoplasmic THRβ1 strongly correlate positively with CD133 and N-cadherin, without any differential effect according to their subcellular location.…”

Thyroid hormone receptor beta inhibits the PI3K-Akt-mTOR signaling axis in anaplastic thyroid cancer via genomic mechanisms

“…TRβ has shown to be a potent tumor suppressor in several types of cancer including breast and thyroid cancer (15,16,35,36). However, there are only a few tumor suppressive mechanisms delineated in the literature, which include TRβ-mediated JAK1/STAT1 activation and binding to p85⍺ (15,20,35).…”

Thyroid Hormone Receptor Beta as Tumor Suppressor: Untapped Potential in Treatment and Diagnostics in Solid Tumors

“…These TRβ-expressing tumors showed evidence of reduced PI3K-Akt signaling and less blood vessel formation compared to tumors without TRβ expression. Most recently, TRβ restoration has been shown to suppress growth and migration in colorectal cancer cells [17], and block cancer stem cell out growth in luminal A breast cancer cell lines [18]. Our lab demonstrated that restoration of TRβ in anaplastic thyroid cancer cells re-programs the transcriptome, promotes apoptosis, and suppresses many of their aggressive phenotypic traits [19].…”

“…There was also a decrease in vascular endothelial growth factor (VEGF) levels which stimulates endothelial cells to promote angiogenesis by way of the PI3K pathway, further implicating a broad-spectrum tumor suppressive role of TRβ. Additionally, TRβ transduction resulted in reduced autocrine signaling in an MCF-7 model [18]. TRβ-T3 decreased expression of vascular endothelial growth factor receptor 9 (FGFR9) and cognate ligands FGF3 and FGF4, while blunting estrogen-mediated induction of FGF9.…”