Thyroid Hormone Receptors and their Role in Cell Proliferation and Cancer

Abstract

The thyroid hormone receptors, TRα and TRβ, are ligand-dependent transcription factors that regulate gene expression by recruitment of coactivators and corepressors. These receptors play an important role in normal and malignant cell proliferation. Particularly, we have shown that TRs antagonize ras-dependent proliferation, transformation and tumorigenesis in fibroblasts. Furthermore, expression of TRβ in human cancer cells retards tumor growth and inhibits invasiveness, extravasation and metastasis formation in euthyroid nude mice. When cells are inoculated into hypothyroid hosts, tumor growth is retarded, but tumors that do grow are more invasive and metastatic growth is enhanced. Increased malignancy of skin tumors is found in mice lacking TRs, further demonstrating the role of these receptors as inhibitors of tumor progression and suggesting that they represent a potential therapeutic target in cancer. TRs have a dual effect on proliferation, because they are required for proliferation of normal hepatocytes or keratinocytes, while acting as inhibitors of tumor progression.