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Thyroid Hormone Receptor β1 Acts as a Potent Suppressor of Tumor Invasiveness and Metastasis

¹ Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid; ² Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid; ³ Cutaneous Disease Modelling Unit and ⁴ Molecular Oncology Unit, Division of Biomedicine, CIEMAT, Madrid, Spain and ⁵ Department of Cell and Molecular Biology, Karolinska Institutet. Stockholm, Sweden

Requests for reprints: Ana Aranda, IIB, CSIC-UAM Arturo Duperier 4, 28029 Madrid, Spain. Phone: 34-91-585-4453; Fax: 34-91-585-4401; E-mail: aaranda{at}iib.uam.es.

Key Words: invasiveness • metastasis • thyroid hormone receptor

Loss of thyroid hormone receptors (TR) is a common feature in some tumors, although their role in tumor progression is currently unknown. We show here that expression of TRβ1 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. In cultured cells, TRβ1 abolishes anchorage-independent growth and migration, blocks responses to epidermal growth factor, insulin-like growth factor-I, and transforming growth factor β, and regulates 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. [Cancer Res 2009;69(2):501–9]