Thyroid hormone receptors (TRs) are ubiquitously expressed ligand-dependent transcription factors that are critical for thyroid hormone regulation of growth development and metabolism. Thyroid cancer is the most common endocrine malignancy with an increasing incidence over the past few decades. Increased surveillance, lifestyle, and environmental factors likely contribute to this increase. Discriminating between indolent and aggressive tumors is critical for diagnostics, clinical management, as well as development of new therapeutic strategies. Aberrant TRs not only disrupt development but are common events in endocrine-related cancers. In particular, dysregulation of the TRβ isoform through point and frameshift mutations as well as epigenetic silencing is established in breast, thyroid, and other tumors.
Restoration of functional TRβ reduces tumor growth in xenograft studies. Of clinical importance, higher levels of TRβ are correlated with improved outcomes in triple-negative breast cancer. Thus, TRs are not only critical for coordinated development and growth but are also integral to prohibiting cellular transformation, tumor development and metastatic growth. The mechanisms for this regulation are not yet known. TRs interact with a variety of co-regulators at DNA response elements to moderate gene expression and genomic activity. Evidence is emerging that TRs, with or without ligand, modify chromatin associated proteins such as histones and chromatin associated with ATPases to effect changes in gene transcription. Thyroid hormones and TRs can also elicit rapid responses through non-genomic cellular effects including regulation of phosphoinositol-3-kinase (PI3K) and mitogen-activated protein kinases (MAPKs) activities, but the role in tumorigenesis is not elucidated.
Our central focus is to unravel the fundamental genomic and epigenomic mechanisms of TR action in development and tumorigenesis. We have recently established a novel genomic signaling pathway in thyroid and breast cancer cells where TRβ represses the expression of an oncogene, Runx2. Runx2, a member of the runt-related family of transcription factors, is important in coordinated development and is an established promoter of tumorigenesis and metastases in breast, thyroid and other tumor types. In thyroid and breast cancers, the PI3K-Akt is activated. Akt phosphorylates Runx2 to increase its activity and metastatic signaling in breast cancer. Moreover, TRβ is known to inhibit the PI3K-Akt activity correlated with tumor progression but the mechanism is not delineated. These observations implicate TRβ inhibition of PI3K-Akt suppression of Runx2 activity in a non-genomic regulation in both breast and thyroid cancers.
Our current research goals:
Establish the genomic, epigenomic and non-genomic mechanisms by which TRβ blunts Runx2 promotion of tumor growth in both thyroid and breast cancers.
Elucidate the dynamic and reciprocal relationships between the nuclear microenvironment, nuclear architecture and TRβ mediated gene expression in thyroid and breast cancer.
Establish the molecular profiles of indolent and aggressive papillary microcarcinomas of the thyroid in collaboration with Dr. Sidiropoulos, Director of Molecular Pathology.
Determine the impact of environmental endocrine disruptors, e.g. bisphenol A, on TR mediated actions in development and tumorgenesis.
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- Hong D, Fritz AJ, Gordon JA, Tye CE, Boyd JR, Tracy KM, Frietze SE, Carr FE, Nickerson JA, Van Wijnen AJ, Imbalzano AN, Zaidi SK, Lian JB, Stein JL, Stein GS. RUNX1-dependent mechanisms in biological control and dysregulation in cancer. J Cell Physiol. 2019 Jun; 234(6): 8597-8609. doi: 10.1002/jcp.27841. PMID: 30515788, PMCID: PMC6395522
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- Hanley JP, Jackson E, Morrissey LA, RIzzo DM, Sprague BL, Sarkar IN, Carr FE. Geospatial and temporal analysis of thyroid cancer incidence in a rural population. Thyroid 2015; 25(7): 812-822. doi: 10.1089/thy.2015.0039. PMID: 25936441, PMCID: PMC4507126
- Sidiropoulos N, Crothers J, Balla A, Dragon J, Carr FE. Molecular Tumorigenesis of Papillary Thyroid Microcarcinoma. International Thyroid Congress, Orlando, FL. October 2015