Dr. Cheng and her team are using multi-disciplinary approaches to understand the biology of thyroid hormone nuclear receptors (TR) and to elucidate the molecular actions of thyroid hormone receptor mutants in human disease. Dr. Cheng employs classical biochemistry, cell biology, immunology, and molecular biology methods in her studies. Additionally, she utilizes cutting-edge approaches such as single-cell RNA-seq, RNAScope, and GeoMX DSP to achieve her research goals. Her current research programs concentrate on two major areas.
Elucidation of the molecular actions of thyroid hormone receptor (TR) mutants in hypothyroidism and resistance to thyroid hormone (RTH)
TRs are thyroid hormone (T3)-dependent transcription factors critical in growth, differentiation, development, and maintaining metabolic homeostasis. These TRs originate from alpha and beta genes, which encode three major T3-binding TRs: alpha1, beta1, and beta2. TRs have a pivotal role, mutations of TRbeta cause RTHbeta, and mutations of TRalpha1 cause RTHalpha. Patients suffering from RTHbeta and RTHalpha exhibit distinct clinical manifestations due to these thyroid hormone receptors' specific functions and roles. As a result, they present with different symptoms. Dr. Cheng and her team created two mouse models by targeting a mutant known as PV to the Thrb and Thra genomic loci (ThrbPV and Thra1PV mice, respectively). These mice exhibit distinct phenotypes, mirroring the conditions observed in RTHbeta and RTHalpha patients. Extensive phenotypic characterization of these two mutant mice revealed that molecular actions of TR mutants are isoform-dependent, leading to different human diseases. Further, TRalpha mutants cause more deleterious effects than TRbeta mutants. Current studies aim to uncover other not-yet-reported defects due to mutation of the THRA gene, such as high mortality and female infertility. These mouse models are being used not only to dissect the distinct molecular actions of TR mutant isoform in vivo and identify potential therapeutic targets. Significantly, these models advance the understanding of the abnormal regulation of other mutated nuclear receptors and transcription factors in human disease.
Dissecting the molecular genetics of thyroid carcinogenesis and identifying potential molecular targets for therapeutics
We discovered a novel molecular action of the TRbetaPV mutant, acting as an oncogene in thyroid cancer, breast cancer, and pituitary tumors. We created mouse models of metastatic follicular thyroid cancer (ThrbPV/PV and ThrbPV/PVPten+/- mice) and anaplastic thyroid cancer (ThrbPV/PVKrasG12D) to dissect the molecular genetic events underlying thyroid carcinogenesis. 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, Molecular and Cellular Biology, Endocrine-Related Cancer, and Neoplasia, we have reported the identification of several aberrant signaling pathways during thyroid carcinogenesis. Several potential targets were identified and tested in these preclinical mouse models to translate them for clinical testing. Our current studies aim to understand the roles of cancer stem cells in chemo resistance and recurrence in anaplastic thyroid cancer, a very aggressive cancer with high mortality and minimal treatment options.
Our collaborators are Dr. Paul Meltzer and Lalage Wakefield, National Cancer Institute; Dr. Yunbo Shi, National Institute of Child Health and Human Development; Dr. Suk Jo Young of Chungnam, National University Hospital, Daejeon, South Korea; Dr. Graham Williams of Imperial College of London, London, UK; Dr. Matthew Ringel of Ohio State University; Dr. Ana Aranda, University Autonoma de Madrid, Spain; Lars Grontved, University of Southern Denmark, Denmark; Claudia G Pellizas, University National de Cordoba, Argentina; and Anita Boelen, University of Amsterdam, the Netherlands.
Dr. Sheue-yann Cheng obtained her Ph.D. from the University of California, San Francisco Medical Center. She received her postdoctoral training at the University of Chicago and the National Institute of Diabetes and Digestive and Kidney Diseases. She joined the NCI as a principal investigator in 1979 and was promoted to Section Chief in 1991. She was promoted to the rank of senior investigator in 2016. Dr. Cheng is well recognized nationally and internationally for her outstanding work in understanding the biology of thyroid hormone nuclear receptors and the molecular actions of mutant thyroid hormone receptors. For her scientific accomplishments, she was awarded the NIH Merit Award for outstanding achievements, the Scientific Achievement Award from the Chinese Medical and Health Association, the Charles Harkin Award of the NCI, the Sidney H. Ingbar Distinguished Lectureship Award of the American Thyroid Association, and the Abbott Thyroid Research Clinical Fellowship Mentor Award of The Endocrine Society. She is a recipient of John B. Stanbury Thyroid Pathophysiological Medal of the American Thyroid Association.She served as a regular member of the NIH Molecular and Cellular Endocrinology Study Session and as an advisor for Howard Hughes Medical Institute-NIH Research Scholars. She served as a Women Scientist Advisor of the Center of Cancer Research, NCI. Currently she is an Associate Editor of Thyroid, Associate Editor-in-Chief of the American Journal of Cancer Research, Associate Editor of Frontier-Endocrinology-Thyroid and also is on the Editorial Boards of several prominent journals. Dr. Cheng focuses on understanding the biology and molecular actions of thyroid hormone receptors in health and disease as described in her work above.
- 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 Thursday, July 27, 2023