The nuclear corepressor 1 and the thyroid hormone receptor β suppress breast tumor lymphangiogenesis

Martínez-Iglesias, Olaia; Olmeda, David; Alonso-Merino, Elvira; Gómez-Rey, Sara; Gonzalez-Lopez, Ana M.; Luengo, Enrique; Soengas, Marı́a S.; Palacios, José; Regadera, Javier; Aranda, Ana

doi:10.18632/oncotarget.12978

Cited by 15 publications

(17 citation statements)

References 49 publications

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“…Clinical studies have shown that elevated TRb levels are also associated with a better prognosis and overall survival in other types of breast tumors (52,53). Furthermore, expression of TRb in triple-negative breast cancer cells reduces tumor growth and has a strong inhibitory effect on invasion and metastasis formation in immunodeficient mice (54)(55)(56)(57). Whether or not TRb could regulate CSC biology by an ERindependent mechanism in other types of mammary tumors is an intriguing possibility that remains to be studied.…”

Section: Discussionmentioning

confidence: 99%

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

López-Mateo

Alonso-Merino

Suárez-Cabrera³

et al. 2020

Thyroid

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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.

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Section: Discussionmentioning

confidence: 99%

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

López-Mateo

Alonso-Merino

Suárez-Cabrera³

et al. 2020

Thyroid

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“…VEGF-C [18] IL-6 [19] Ring finger protein 180 [20] ID-1 [21] Sonic hedgehog [22] iNOS [23] Melanoma VEGF-C [24,25] FAS [24] Microphthalmia-associated transcription factor [25] c-Jun N-terminal kinase and p38/mitogen-activated protein kinase [25] Integrin α4β1 [26,27] FLT4 [28] High fat diet -CCL18, CCL21/CCR7 axis [ [34] Ezrin [34] COX-2 [35,38] Prostaglandin E2 and E receptor [35] NCoR and TRβ1 [36] TAMs [39,40] IL-24 [41] ELK3 [37] S1P [42] SEMA7a [43] DcR3 [44] Sulf2 [45] Mast cell density [46]…”

Section: Accepted Manuscript Cancer Markers Gastricmentioning

confidence: 99%

“…After activation of VEGFR-3, Homeobox transcription factor HOXD10 is activated, and is involved in lymphatic endothelial cell migration and formation of cord-like structures, as it regulates the expression of VE-cadherin, claudin-5, and nicotinamide adenine dinucleotide phosphate oxidase 3 (NOS3) [89]. Examples of cancers that have upregulated VEGF-C include melanoma, squamous cell carcinomas, gastric, cervical, breast, gallbladder, colon, lung, ovarian, chondrosarcoma, pancreatic, neuroblastoma, and prostate cancers [18][19][20]24,25,28,32,[34][35][36]41,47,50,51,54,55,59,62,63,71,90]. Many variables can increase VEGF-C expression in cancers.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Other key factors that increase lymphangiogenesis by altering VEGF-C expression include nuclear receptor corepressor 1 (NCoR) and the thyroid hormone receptor β1 (TRβ1), E26 transformation-specific (ETS) domain-containing protein Elk-3 (ELK3), and high mobility group box 1 protein. Ncor and TRβ1 decrease the invasiveness of tumors [36]. Martinez-Iglesias et al studied the means by which this occurs and found that NCoR and TRβ1 decrease VEGF-C and VEGF-D expression in breast cancer cells, decreasing lymphangiogenesis and lymph node metastases in a tumor xenograft mouse model.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Lymphatic changes in cancer and drug delivery to the lymphatics in solid tumors

Cote

Rao

Alany

et al. 2019

Advanced Drug Delivery Reviews

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Although many solid tumors use the lymphatic system to metastasize, there are few treatment options that directly target cancer present in the lymphatic system, and those that do are highly invasive, uncomfortable, and/or have limitations. This review gives a brief overview of lymphatic function and anatomy, discusses changes that befall the lymphatics in cancer and the mechanisms by which these changes occur, and presents limitations for drug delivery to the lymphatic system. We then go on to summarize relevant techniques and new research for targeting cancer populations in the lymphatics and enhancing drug delivery intralymphatically, including intralymphatic injections, isolated limb perfusion, passive nano drug delivery systems, and actively targeted nanomedicine.

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“…The abovementioned effects of m-TRβ1 were significantly stronger than those of TRβ1. Studies have shown that TRβ1 can inhibit the proliferation and migration of hepatocarcinoma cells and other cancer cells [ 2 , 4 , 6 , 15 , 23 – 25 ]. Cell apoptosis is a complicated biological process that is associated with complex signaling pathway responses.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of modified human TRβ1 suppresses the growth of hepatocarcinoma SK-hep1 cells in vitro and in xenograft models

et al. 2018

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Association studies suggest that TRβ1 functions as a tumor suppressor. Thyroid hormone receptors (TRs) mediate transcriptional responses through a highly conserved DNA-binding domain (DBD). We previously constructed an artificially modified human TRβ1 (m-TRβ1) via the introduction of a 108-bp exon sequence into the corresponding position of the wild-type human TRβ1 (TRβ1) DBD. Studies confirmed that m-TRβ1 was functional and could inhibit the proliferation of breast cancer MDA-MB-468 cells in vitro. To understand the role of m-TRβ1 in liver tumor development, we adopted a gain-of-function approach by stably expressing TRβ (m-TRβ1 and TRβ1) genes in a human hepatocarcinoma cell line, SK-hep1 (without endogenous TRβ), and then evaluated the effects of the expressed TRβ on cancer cell proliferation, migration, and tumor growth in cell-based studies and xenograft models. In the presence of 3,5,3-l-triiodothyronine (T3), the expression of TRβ in SK-hep1 cells inhibited cancer cell proliferation and impeded tumor cell migration through the up-regulation of 4-1BB, Caspase-3, and Bak gene expression; down-regulation of Bcl-2 gene expression; and activation of the Caspase-3 protein. TRβ expression in SK-hep1 led to less tumor growth in xenograft models. Additionally, the anti-tumor effect of m-TRβ1 was stronger than that of TRβ1. These data indicate that m-TRβ1 can act as a tumor suppressor in hepatocarcinoma and its role was significantly better than that of TRβ1.

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The nuclear corepressor 1 and the thyroid hormone receptor β suppress breast tumor lymphangiogenesis

Cited by 15 publications

References 49 publications

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

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

Lymphatic changes in cancer and drug delivery to the lymphatics in solid tumors

Overexpression of modified human TRβ1 suppresses the growth of hepatocarcinoma SK-hep1 cells in vitro and in xenograft models

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