Date of Award

2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cellular, Molecular and Biomedical Sciences

First Advisor

Frances E. Carr

Second Advisor

Karen C. Glass

Abstract

Dysregulation of the tumor suppressor thyroid hormone receptor beta (TRβ) is a frequent event in a number of solid tumors. As a nuclear hormone receptor, the primary function of TRβ is to regulate transcriptional activity in a ligand-dependent manner. However, TRβ activity is not well-defined and the pathways it regulates are not yet fully delineated. The two cancer types where TRβ is best studied are thyroid cancer and breast cancer. Interestingly, thyroid cancer is a risk factor for breast cancer and breast cancer is a risk factor for thyroid cancer, suggestive of an etiological link. Determining the molecular mechanisms of a tumor suppressor shared by both diseases may reveal critical tumor suppressive pathways.

First, in order to discover novel pathways that are regulated by TRβ, TRβ was stably overexpressed in an anaplastic thyroid cancer (ATC) cell line through lentiviral transduction. TRβ has not previously been overexpressed in ATC and, through triiodothyronine (T3) stimulation, TRβ repressed pro-malignant phenotypes including cellular growth, migration, and stemness. Additionally, TRβ and T3 promoted apoptosis. RNA-sequencing and subsequent analysis revealed novel TRβ-mediated STAT1 stimulation. Additionally, unmodified anaplastic thyroid cancer cells were sensitive to treatment with a STAT1 agonist.

Next, to determine if there is common transcriptional signaling between different types of solid tumors, the TRβ-RUNX2 pathway was examined in breast cell lines. In thyroid cancer, TRβ represses expression of the pro-metastatic transcription factor RUNX2. In addition to promoting thyroid cancer, aberrant overexpression of RUNX2 is a driver of breast carcinogenesis. This informed the hypothesis that TRβ-mediated repression of RUNX2 and resultant signaling is common to thyroid and breast cancers. T3 treatment reduced RUNX2 expression in breast cell lines. Additionally, TRβ bound to thyroid hormone response elements in the RUNX2 promoter, the same mechanism of action for T3-mediated repression as in thyroid cells.

Lastly, to more broadly address mechanisms mediated by TRβ, TRβ was stably overexpressed in a basal-like aggressive breast cancer cell line. TRβ is already known to be able to repress tumor growth and metastasis in this type of cancer. However, the specific molecular mechanisms driving the anti-tumor phenotype are not well delineated. In order to determine which molecular signaling pathways are regulated by TRβ, RNA-sequencing was performed. TRβ induced a more epithelial profile of these cells, in contrast to the typically mesenchymal nature of basal-like breast cancer. Novel TRβ-mediated repression of pro-invasive cytokeratins was found. The genes regulated by TRβ in these cells were also compared to the findings in ATC. The set of common genes included chromatin remodelers and enzymes involved in stearate biosynthesis; the latter is known to have anti-cancer properties and may be an important driver of TRβ-mediated tumor suppression in both breast and thyroid cancers.

Language

en

Number of Pages

241 p.

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