Thyroid Hormone Receptors (TRs) in Cancer: New Insights on TR DNA Binding

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 338-365-Metabolic & Stress Receptors in Energy Homeostasis
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-348
Nina V. Titova*1, Jonathan Deans1, Bin Fang1, Martin L. Privalsky2 and Frances M. Sladek1
1University of California, Riverside, CA, 2UC Davis, Davis, CA
Thyroid hormone receptors (TRs) play a crucial role in controlling glucose and lipid metabolism as well as energy homeostasis in most tissues. Metabolism also plays a critical role in cancer, where enhanced aerobic glycolysis distinguishes cancer from the normal tissue.  Mutations in TR genes have been found in many types of human cancer: e.g., 32% of renal clear cell carcinomas (RCCC) have TRβ1 mutations while 14% have TRα1 mutations(1); TRα1 and TRβ1 are mutated in hepatocellular carcinoma (HCC) at a frequency of 65% and 76%, respectively(2). However, the exact role of TRs in cancer metabolism is unclear, and much remains to be learned about TR target genes.

In the Nuclear Receptor DNA Binding Project we use protein binding microarrays (PBMs) to comprehensively define the DNA binding specificity of NRs ( Here we present PBM data on wild type human TRα1, TRβ1 and TRβ2 binding 1000’s of unique DNA sequences in the presence and absence of their heterodimeric partner retinoid X receptor (RXRα) and triiodothyronine (T3).  We compare the binding specificity of different TR mutants found in human HCC [hcI-TRα1 (K74E,A264V), hcM-TRα1 (K74R,M150T,E159K)], human RCCC [rc6-TRα1 (I116N,A225T,M388I), rc15-TRβ1 (K155E,K411E)] and oncogenic gag-v-Erb-A. Finally, we identify affinity altering single nucleotide polymorphisms (aaSNPs) in TR binding sites for TRα1, TRβ1 and TRβ2 heterodimers. These results will help characterize potential TR target genes in normal and cancerous cells, elucidate the mechanism by which TR mutants contribute to cancer and potentially identify populations susceptible to TR action. Our results could also potentially have implications for therapeutics.

(1) Kamiya Y et al., Carcinogenesis 2002; 23:25. (2) Lin K.H. et al., Mol. Carcinog. 1999; 26:53

Nothing to Disclose: NVT, JD, BF, MLP, FMS

*Please take note of The Endocrine Society's News Embargo Policy at

Sources of Research Support: NIH Grant DK094707 awarded to FMS