A major contributor to altered gene expression and chromatin reorganization in endocrine-related cancers is nuclear receptor signaling. Nuclear hormone receptors (NRs) are ligand-activated transcription factors that regulate diverse physiological functions including development, reproduction, homeostasis, and metabolism. They also represent an important group of prognostic indicators and therapeutic targets in hormone-driven cancers. In the F99 phase of this proposal, my focus is on studying the impact of dysregulation of the transcription factor TR?, a member of the thyroid hormone receptor (TR) family in dedifferentiated thyroid tumors. The current prognosis for patients with resistant or recurrent thyroid cancer is extremely poor. Due to the lack of effective therapies, patients with advanced or metastatic thyroid cancer have a higher mortality rate than all other endocrine cancers combined. Importantly, restoration of TR? function in malignant cells decreases tumor growth in xenograft studies. Despite a recognized role as a tumor suppressor, the mechanisms by which TR? regulates tumor growth are not clear. Therefore, I will address the critical need for a deeper understanding of thyroid hormone receptor beta (TR?) tumor suppressor mechanisms to inform the development more effective therapies for aggressive thyroid cancer. The directly regulated genes of TR? will be defined through an integrated analysis of genome-wide binding and global gene expression data in thyroid cells. I will also determine the role that BRG1 plays in facilitating thyroid hormone induced chromatin remodeling, and its importance for maintenance of a normal transcriptional profile in thyroid cells. These data will provide us with key insights into thyroid cancer growth and progression, and allow for new target pathways to be explored as therapeutic options. In the K00 phase, I propose to pursue my broader interests in nuclear receptor mediated epigenetic programming and crosstalk in cancer in an environment which will allow me to expand my expertise hormone-mediated gene regulation and my technical skill set. I have identified a critical gap in our current understanding of the impact of hormone signaling on epigenetic regulatory mechanisms and changes in chromatin in structure. I plan to build upon my current training to develop a project that addresses the epigenetic mechanisms by which hormone signaling affects cancer cell identity, and translate these findings into clinically meaningful signatures. This work will add depth to our current understanding of nuclear receptor biology, and advance our ability to effectively treat hormone-dependent cancers with therapies that target nuclear receptors.

Public Health Relevance

A major contributor to altered gene expression and chromatin reorganization in endocrine-related cancers is nuclear receptor signaling. Hormone therapies are currently the cornerstone of treatment for most patients, however, a deeper understanding of nuclear receptor regulation of epigenetics will help combat tumor recurrence and therapeutic resistance. The proposed work will not only add depth to our current understanding of nuclear receptor biology, but also advance our ability to effectively treat hormone-dependent cancers with therapies that target nuclear receptors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Project #
5F99CA245796-02
Application #
10016237
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Eljanne, Mariam
Project Start
2019-09-11
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405