Sheue-yann Cheng, Ph.D.
Laboratory of Molecular Biology
Building 37, Room 5128
Bethesda, MD 20892
Thyroid Hormone Receptor (TR) Mutants: Molecular Actions and Roles in Disease
Our research goals are to elucidate the molecular actions of thyroid hormone receptor (TR) mutants and understand their roles in disease. TRs are thyroid hormone (T3)-dependent transcription factors that are critical in growth, differentiation, and development, and in maintaining metabolic homeostasis. TRs are derived from two genes, alpha and beta, that encode four T3-binding TRs: alpha1, beta1, beta2, and beta3. Given the pivotal roles of TRs, it is reasonable to expect that their mutations could lead to deleterious effects. Indeed, mutations of the THRB gene are known to cause a genetic disease, resistance to thyroid hormone (RTH). Very recently, patients with severe hypothyroidism were found to have mutations in the THRA gene. To understand how TRbeta and TRalpha mutants act in vivo to cause these disease in patients, we have developed genetically engineered mouse models (ThrbPV mice and Thra1PV mice, respectively). These mouse models are being used not only to dissect the molecular actions of TR mutant isoforms in vivo, but also to identify potential therapeutic targets. Importantly, these models serve to advance understanding of the abnormal regulation of other mutated nuclear receptors and transcription factors in human disease.
In addition, we have also created mouse models to studying the molecular genetic events underlying thyroid carcinogenesis. Follicular thyroid carcinoma is an aggressive form of thyroid cancer that shows a propensity for blood-borne metastasis. While overall survival of patients with this type of tumor is generally better than for cancers in many other organs, approximately 30% of patients do not survive beyond 20 years, even with successful primary surgical therapy. The genetic basis for this metastatic behavior is not fully understood. We have created the only mouse model for follicular thyroid carcinoma (ThrbPV/PV mouse) in order to identify genetic changes underpinning metastatic thyroid carcinogenesis and progression, and to identify potential molecular targets for prevention and treatment of invasive thyroid cancer.
In a series of publications in high-impact peer-reviewed journals, such as Proceedings of the National Academy of Sciences USA, Cancer Research, Journal of Clinical Investigation, Oncogene, and Molecular and Cellular Biology, we have reported the identification of several altered signaling pathways, involving the activation of tumor promoters such as cyclin D1, beta-catenin, phosphatidylinositol 3-kinase (PI3K), AKT and pituitary tumor transforming gene, and repression of tumor suppressors such as peroxisome proliferator activating receptor gamma (PPARgamma). These altered signaling pathways identified during thyroid carcinogenesis in ThrbPV/PV mouse mice are consistent with the changes reported for carcinogenesis in the human thyroid. More recently, we have also developed a mouse model that exhibits undifferentiated thyroid cancer (anaplastic thyroid cancer). This newly developed mouse model will be used to elucidate the molecular basis underlying undifferentiated thyroid cancer. Currently the treatment modality for undifferentiated thyroid cancer is very limited. This mouse model could potentially be used as a preclinical mouse model to test novel therapeutics and to develop more effective treatment modalities.
Our collaborators are Dr. Mark Willingham, Wake Forest University School of Medicine, Winston-Salem, NC; Dr. Paul Meltzer, Human Genome Research Institute; Dr. Thomas Klonisch of the University of Manitoba, Winnipeg, Canada; Dr. J. Paul Banga, The Rayne Institute, London, UK; Dr. SuK Jo Young of Chungnam National University Hospital, Daejeon, South Korea; Dr. Graham Williams of Imperial College of London, London, UK; Dr. James D. Lechleiter of the University of Texas Health Science Center at San Antonio, Texas; Dr. Doug Forrest of the National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK); Dr. Caroline Kim of Boston University; and Dr. Matthew Ringel of Ohio State University.
Enomoto K, Zhu X, Park S, Zhao L, Zhu YJ, Willingham MC, Qi J, Copland JA, Meltzer P, Cheng SY. Targeting MYC as a Therapeutic Intervention for Anaplastic Thyroid Cancer. J Clin Endocrinol Metab. 2017;102(7):2268-2280.
Zhu X, Enomoto K, Zhao L, Zhu YJ, Willingham MC, Meltzer P, Qi J, Cheng SY. Bromodomain and Extraterminal Protein Inhibitor JQ1 Suppresses Thyroid Tumor Growth in a Mouse Model. Clin Cancer Res. 2017;23(2):430-440.
Grøntved L, Waterfall JJ, Kim DW, Baek S, Sung MH, Zhao L, Park JW, Nielsen R, Walker RL, Zhu YJ, Meltzer PS, Hager GL, Cheng SY. Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling. Nat Commun. 2015;6:7048.
Fozzatti L, Kim DW, Park JW, Willingham MC, Hollenberg AN, Cheng SY. Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor α. Proc Natl Acad Sci U S A. 2013;110(19):7850-5.
Fozzatti L, Lu C, Kim DW, Park JW, Astapova I, Gavrilova O, Willingham MC, Hollenberg AN, Cheng SY. Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1). Proc Natl Acad Sci U S A. 2011;108(42):17462-7.
Related Scientific Focus Areas
Genetics and Genomics
Molecular Biology and Biochemistry
This page was last updated on July 24th, 2017