Dr. Cheng pioneered the development of mouse models to understand the molecular basis of diseases due to mutations of thyroid hormone receptors. Her intensive studies of mouse models of hypothyroidism and resistance to thyroid hormone resulted in the discovery that mutations of thyroid hormone receptor subtypes lead to different human diseases. Dr. Cheng also developed preclinical mouse models of metastatic follicular thyroid cancer. She focuses on the elucidation of altered signaling pathways in metastatic thyroid cancer to understand the molecular genetics underlying thyroid carcinogenesis. She identified molecular targets for potential treatment of thyroid cancer.
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.
- Proc. Natl. Acad. Sci. U.S.A. 103: 1780-5, 2006. [ Journal Article ]
- Proc. Natl. Acad. Sci. U.S.A. 108: 17462-7, 2011. [ Journal Article ]
SKI-606, an Src inhibitor, reduces tumor growth, invasion, and distant metastasis in a mouse model of thyroid cancer.Clin. Cancer Res. 18: 1281-90, 2012. [ Journal Article ]
Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor alpha.Proc. Natl. Acad. Sci. U.S.A. 110: 7850-7855, 2013. [ Journal Article ]
- Hum. Mol. Genet. 23: 2651-64, 2014. [ Journal Article ]
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 senior investigator in 1979 and was promoted to Section Chief in 1991. Dr. Cheng is a recipient of 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 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. Currently she is a Women Scientist Advisor of the Center of Cancer Research, NCI and is on the Editorial Boards of several prominent journals. Dr. Cheng research focuses on understanding the biology and molecular actions of thyroid hormone receptors in health and disease. Dr. Cheng describes her current research below.
|Cho Rong Han Ph.D.||Postdoctoral Fellow (Visiting)|
|Erik Holmsen||Postbaccalaureate Fellow|
|Minkyung Kang Ph.D.||Postdoctoral Fellow (Visiting)|
|Sunmi Park Ph.D.||Postdoctoral Fellow (Visiting)|
|Li Zhao Ph.D.||Research Biologist|
|Xuguang Zhu Ph.D.||Staff Scientist|