TOPIC: Thyroid hormone receptor
Title: Thyroid hormone receptor alpha1 acts as a potent suppressor of tumor invasiveness and metastasis.
Authors: Martinez-Iglesias O, Garcia-Silva S, Tenbaum SP, Regadera J, Larcher F, Paramio JM, Vennstrom B, & Aranda A.
Reference: Cancer Research 69: 501-509, 2009
Loss of thyroid hormone receptors (TR) is a common feature in some tumors, although their role in tumor progression is currently unknown. The authors show that expression of TRb1 in hepatocarcinoma and breast cancer cells reduces tumor growth, causes partial mesenchymal-to-epithelial cell transition, and has a striking inhibitory effect on invasiveness, extravasation, and metastasis formation in mice.
SK-hep1 (hepatocellular carcinoma) and MDA (breast cancer cells) cells were transfected with a retrovirus containing the human TRb1 isoform. Tumor growth and metastases were measured in vivo in nude mice. In addition, in vitro analysis of colony formation, growth in suspension and invasiveness were measured in MDA and SK cultured cells with and without expression of the TRb1.
In cultured cells, TRb1 abolishes anchorage-independent growth and migration, blocks responses to epidermal growth factor, insulin-like growth factor-1, and transforming growth factor B, and regulates the expression of genes that play a key role in tumorigenicity and metastatic growth. The receptor disrupts the mitogenic action of growth factors by suppressing activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling pathways that are crucial for cell proliferation and invasiveness. Furthermore, increased aggressiveness of skin tumors is found in genetically modified mice lacking TRs, further demonstrating the role of these receptors as inhibitors of tumor progression.
These results define a novel role for the thyroid hormone receptor as a metastasis suppressor gene, providing a starting point for the development of novel therapeutic strategies for the treatment of human cancer.
Thyroid hormone receptors are pokies voyeur gallery nuclear transcription factors that mediate thyroid hormone action on gene expression. Well known are the roles these receptors play in mediating the metabolic and developmental effects of thyroid hormone. TRs, however, can negatively regulate gene promoters as it does in the liganded state with respect to TSH and TRH. In addition, TRs can negatively regulate target gene promoters that carry the AP-1 site, which regulates the expression of genes involved in oncologic transformation and cell proliferation. The role of TRs in tumor progression or growth is unknown.
The authors hypothesized that down regulation of AP-1 by receptors would prevent cell proliferation. It has been well established that there is reduced expression of TRb1 in hepatocellular carcinoma and breast cancer cell lines, which show elevated RAS activation. Uninhibited RAS activation results in tumor formation. Therefore, it would make sense that TRb1 may act as an “anti-RAS” factor and inhibit tumorogenesis.
The present article demonstrates that absence of TRb1 results in growth and metastasis of hepatocellular and breast cancers in nude mice. While this was already previously known, what is new and exciting in this report is that the investigative team can strongly suppress invasiveness and metastasis by expressing TRb1 in the ‘SK-hep1’ and ‘MDA’ cell line models of cancer. While we have not observed an increase in cancers in mice with deletion of TRb and TRa, as would be the expected extension of these results, S.-Y. Cheng’s laboratory at the N.I.H. has shown that the ‘TRb PV’ knock-in model does have an increased incidence of thyroid cancer with significant metastasis, suggesting that the role of TR in tumor growth may be a more general phenomena and potentially a useful target for novel strategies in cancer therapy.
Summary and Commentary prepared by Roy Weiss (Related to Chapter 3 of TDM)