Extrathyroidal Expression of the Thyrotropin Receptor in Epithelial Cancer Cells

Glycoprotein hormone receptors are G-protein-coupled receptors essential for endocrine signaling. Thyroid-stimulating hormone receptor (TSHR), originally expressed in the thyroid gland, has been increasingly detected in various normal and malignant tissues, suggesting a wide range of functions. We hypothesized that extrathyroidal TSHR contributes to tumor development and activation via local stimulators such as thyrostimulin and its subunits. In the present study, TSHR expression was characterized in breast (T47D, MCF7), pancreatic (PL45, BXPC3), and colon (HCT116) cancer cell lines using quantitative real-time PCR, immunohistochemistry, and Western blotting. The sequencing of the TSHR cDNA revealed several novel mutations with potential functional relevance. Notably, missense mutations, Glu362Asp (PL45, HCT116) and Ala380Pro (T47D) were identified in the extracellular hinge region, which is a key domain for ligand binding and receptor activation. Functional interpretation suggests that Glu362Asp may lower the steric barrier, thereby enhancing the receptor sensitivity to non-canonical ligands such as thyrostimulin. In addition, Ile419Leu identified in T47D cells and located within the transmembrane Helix 1 may alter receptor conformation and signaling capacity. Consistent with these findings, variable proliferative responses to bovine thyroid-stimulating hormone (bTSH) were observed across the examined cell lines. Collectively, these results functionally identify relevant TSHR variants in cancer cells and support a model in which extrathyroidal TSHR signaling contributes to tumor progression. Targeting these receptors may represent a novel therapeutic approach.