We read with interest the Review 'G-protein-coupled receptors and cancer' by Dorsam and Gutkind published in Nature Reviews Cancer1. In table 1 the authors state inaccurately that thyrotropin secreting hormone (TSH) and adrenocorticotropin hormone (ACTH) receptors (TSHR and ACTHR, respectively) cause pituitary tumours.
The pituitary gland secretes six polypeptide hormones — ACTH, TSH, growth hormone (GH), gonadotropins (follicle stimulating hormone (FSH) and luteinizing hormone (LH)) and prolactin. These trophic hormones act at their respective target glands (adrenals, thyroid, cartilage, gonads and breast) to regulate peripheral hormone secretion and glandular growth and differentiation2.
TSH is secreted by the pituitary and signals through the TSHR at the thyroid gland to induce thyroid hormone synthesis. Several naturally occurring mutations are found in the TSHR3,4,5. Activating, somatic TSHR mutations cause toxic thyroid adenomas6, and activating, germline TSHR mutations can cause hereditary toxic thyroid hyperplasia7 and familial gestational hyperthyroiditis8. Inactivating, germline TSHR mutations can cause partial or complete resistance to TSH9,10 or isolated central hypothyroidism11. No TSHR mutation is yet known to cause pituitary tumours; moreover, TSHR mutations are unlikely do so, as TSH is secreted by the pituitary and acts at the periphery.
ACTH is secreted by the pituitary gland and acts peripherally at the ACTHR (currently known as melanocortin 2 receptor (MC2R3)) in the adrenal glands to induce adrenal steroid synthesis. An inactivating, germline mutation in MC2R was shown to cause familial glucocorticoid deficiency in 25% of patients with this disease12. A deletion of MC2R was found in two very aggressive undifferentiated adrenocortical tumours13. Adrenal tumours have not been found to harbour gain-of-function mutations of MC2R3,14,15. No MC2R mutation is known to cause pituitary tumours.
References
Dorsam, R. T. & Gutkind, J. S. G-protein-coupled receptors and cancer. Nature Rev. Cancer 7, 79–94 (2007).
Melmed, S. Mechanisms for pituitary tumorigenesis: the plastic pituitary. J. Clin. Invest. 112, 1603–1618 (2003).
Lania, A. G., Mantovani, G. & Spada, A. Mechanisms of disease: mutations of G proteins and G-protein-coupled receptors in endocrine diseases. Nature Clin. Pract. Endocrinol. Metab. 2, 681–693 (2006).
Davies, T. F., Ando, T., Lin, R. Y., Tomer, Y. & Latif, R. Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J. Clin. Invest. 115, 1972–1983 (2005).
Krohn, K. et al. Molecular pathogenesis of euthyroid and toxic multinodular goiter. Endocr. Rev. 26, 504–524 (2005).
Parma, J. et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365, 649–651 (1993).
Fuhrer, D., Wonerow, P., Willgerodt, H. & Paschke, R. Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. J. Clin. Endocrinol. Metab. 82, 4234–4238 (1997).
Rodien, P. et al. Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N. Engl. J. Med. 339, 1823–1826 (1998).
Abramowicz, M. J., Duprez, L., Parma, J., Vassart, G. & Heinrichs, C. Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J. Clin. Invest. 99, 3018–3024 (1997).
Sunthornthepvarakui, T., Gottschalk, M. E., Hayashi, Y. & Refetoff, S. Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N. Engl. J. Med. 332, 155–160 (1995).
Collu, R et al. A novel mechanism for isolated central hypothyroidism: inactivating mutations in the thyrotropin-releasing hormone receptor gene. J. Clin. Endocrinol. Metab. 82, 1561–1565 (1997).
Clark, A. J., McLoughlin, L. & Grossman, A. Familial glucocorticoid deficiency associated with point mutation in the adrenocorticotropin receptor. Lancet 341, 461–462 (1993).
Reincke, M et al. Deletion of the adrenocorticotropin receptor gene in human adrenocortical tumors: implications for tumorigenesis. J. Clin. Endocrinol. Metab. 82, 3054–3058 (1997).
Reincke, M. Mutations in adrenocortical tumors. Horm. Metab. Res. 30, 447–455 (1998).
Beuschlein, F., Fassnacht, M., Klink, A., Allolio, B. & Reincke, M. ACTH-receptor expression, regulation and role in adrenocortial tumor formation. Eur. J. Endocrinol. 144, 199–206 (2001).
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Ben-Shlomo, A., Melmed, S. Pituitary hormone receptors and tumorigenesis. Nat Rev Cancer 7, 722 (2007). https://doi.org/10.1038/nrc2069-c1
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DOI: https://doi.org/10.1038/nrc2069-c1
