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Project description: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 ? (TR?) appears to suppress breast tumor growth and metastasis, we have analyzed the possibility that TR? 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 TR?-expressing MCF-7 cells (MCF7-TR? 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-TR? cultures. T3 also decreased migration and invasion, a hallmark of CSCs. Transcriptome analysis showed downregulation of the estrogen receptor alpha (ER?) 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 TR? in the biology of CSCs that may be related to its action as a tumor suppressor in breast cancer.
| S-EPMC6998057 | biostudies-literature
Project description:Since the thyroid hormone receptor β (TRβ) appears to suppress breast tumor growth and metastasis, we have analyzed the possibility that this receptor could affect cancer stem cell biology using TRβ-expressing MCF-7 cells (MCF7-TRβ cells) treated with the thyroid hormone T3.
2019-12-05 | GSE117949 | GEO
Project description:Since the thyroid hormone receptor β (TRβ) appears to suppress breast tumor growth and metastasis, we have analyzed the possibility that this receptor could affect cancer stem cell biology using mammospheres from TRβ-expressing MCF-7 cells (MCF7-TRβ cells) treated with the thyroid hormone T3.
2019-12-05 | GSE117950 | GEO
Project description:The thyroid hormone receptor β inhibits self-renewal capacity of breast cancer stem cells
| PRJNA483781 | ENA
Project description:The thyroid hormone receptor β inhibits self-renewal capacity of breast cancer stem cells (Adherent MCF7 cells)
| PRJNA483784 | ENA
Project description:The thyroid hormone receptor β inhibits self-renewal capacity of breast cancer stem cells (mammospheres from MCF7 cells)
| PRJNA483782 | ENA
Project description:The capacity of breast cancer cells to form mammospheres in non-adherent serum-free culture is used as a functional characteristic of the self-renewing stem-like cell population. The present studies demonstrate that silencing expression of the MUC1-C oncoprotein inhibits growth of luminal MCF-7 and HER2-overexpressing SKBR3 breast cancer cells as mammospheres. We also show that triple-negative MDA-MB-468 breast cancer cells are dependent on MUC1-C for growth as mammospheres and tumor xenografts. Similar results were obtained when MUC1-C function was inhibited by expression of a MUC1-C(CQCAQA) mutant. Moreover, treatment with the MUC1-C inhibitor GO-203, a cell penetrating peptide that binds to the MUC1-C cytoplasmic domain and blocks MUC1-C function, confirmed the importance of this target for self-renewal. The mechanistic basis for these findings is supported by the demonstration that MUC1-C activates NF-κB, occupies the IL-8 promoter with NF-κB, and induces IL-8 transcription. MUC1-C also induces NF-κB-dependent expression of the IL-8 receptor, CXCR1. In concert with these results, targeting MUC1-C with GO-203 suppresses IL-8/CXCR1 expression and disrupts the formation of established mammospheres. Our findings indicate that MUC1-C contributes to the self-renewal of breast cancer cells by activating the NF-κBIL-8/CXCR1 pathway and that targeting MUC1-C represents a potential approach for the treatment of this population.
| S-EPMC4058032 | biostudies-literature
Project description:Cancer stem-like cells (CSCs) play a key role in maintaining the aggressiveness of hepatocellular carcinoma (HCC), but the cell-biological regulation of CSCs is unclear. In the study, we report that thyroid hormone (TH) promotes cell self-renewal in HCC cells. TH also increases the percentage of CD90?+?HCC cells and promotes drug resistance of HCC cells. By analyzing primary human HCC samples, we found that TR? transcript level is significantly elevated in primary liver cancer and portal vein metastatic tumor, compared to that of adjacent normal liver tissue. Knocking down TR? not only inhibits HCC self-renewal in vitro but also suppresses HCC tumor growth in vivo. Interestingly, treatment of TH leads to activation of NF-?B, which is required for the function of TH on inducing HCC cell self-renewal. We also found TR? and p65 cooperatively drive the expression of BMI1 by co-binding to the promoter region of BMI1 gene. In summary, our study uncovers a novel function of TH signaling in regulating the CSCs of HCC, and these findings might be useful for developing novel therapies by targeting TH function in HCC cells.
| S-EPMC4865859 | biostudies-other
Project description:The purpose of this study was to discover novel nuclear receptor targets in triple-negative breast cancer. Expression microarray, Western blot, qRT-PCR analyses, MTT growth assay, soft agar anchorage-independent growth assay, TRE reporter transactivation assay, and statistical analysis were performed in this study. We performed microarray analysis using 227 triple-negative breast tumors, and clustered the tumors into five groups according to their nuclear receptor expression. Thyroid hormone receptor beta (TR?) was one of the most differentially expressed nuclear receptors in group 5 compared to other groups. TR? low expressing patients were associated with poor outcome. We evaluated the role of TR? in triple-negative breast cancer cell lines representing group 5 tumors. Knockdown of TR? increased soft agar colony and reduced sensitivity to docetaxel and doxorubicin treatment. Docetaxel or doxorubicin long-term cultured cell lines also expressed decreased TR? protein. Microarray analysis revealed cAMP/PKA signaling was the only KEGG pathways upregulated in TR? knockdown cells. Inhibitors of cAMP or PKA, in combination with doxorubicin further enhanced cell apoptosis and restored sensitivity to chemotherapy. TR?-specific agonists enhanced TR? expression, and further sensitized cells to both docetaxel and doxorubicin. Sensitization was mediated by increased apoptosis with elevated cleaved PARP and caspase 3. TR? represents a novel nuclear receptor target in triple-negative breast cancer; low TR? levels were associated with enhanced resistance to both docetaxel and doxorubicin treatment. TR?-specific agonists enhance chemosensitivity to these two agents. Mechanistically enhanced cAMP/PKA signaling was associated with TR?'s effects on response to chemotherapy.
| S-EPMC4418174 | biostudies-literature
Project description:Anaplastic thyroid cancer (ATC) is one of the most aggressive solid cancers in humans, with limited treatment options. Recent studies suggest that cancer stem cell (CSC) activity contributes to therapeutic resistance and recurrence of ATC. We show that the expression of the endogenous thyroid hormone receptor β gene (THRB) is silenced in ATC and demonstrate that the exogenously expressed TRβ suppresses CSC activity. Decitabine is one of the demethylation agents to treat myelodysplastic syndrome and acute myeloid leukemia patients and is currently in clinical trials for hematopoietic malignancies and solid tumors. We aim to show that the re-expression of the endogenous THRB gene by decitabine can attenuate CSC activity to block ATC tumor growth. We treated ATC cell lines derived from human ATC tumors (11T and 16T cells) with decitabine and evaluated the effects of the reactivated endogenous TRβ on CSC activity in vitro and in vivo xenograft models. We found that treatment of 11T and 16T cells with decitabine reactivated the expression of endogenous TRβ, as evidenced by western blot and immunohistochemical analyses. The expressed TRβ inhibited cell proliferation by arresting cells at the S phase, increased apoptotic cell death by upregulation of cleaved caspase-3, and markedly suppressed the expression of CSC regulators, including cMYC, ALDH, SOX2, CD44, and β-catenin. Decitabine also inhibited xenograft tumor growth by suppressing CSC activity, inhibiting cancer cell proliferation, and increasing apoptosis. Our findings suggest that re-expression of the endogenous TRβ is a novel therapeutic approach for ATC via suppression of CSC activity.
| S-EPMC10354538 | biostudies-literature