Date of Award

2016

Degree Name

Biomedical Sciences

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Gary Rankin

Second Advisor

Eric Blough

Third Advisor

Piyali Dasgupta

Fourth Advisor

Todd Green

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is responsive to many exogenous and endogenous ligands. AHR is of particular interest in cancer, and has been shown to play roles in tumor progression. As such, it has received growing attention as a possible chemotherapeutic target. Obesity increases the risk of breast cancer, complicates treatment of breast cancer, and stimulates the growth of larger, more aggressive mammary tumors. Many breast tumors in obese women are estrogen receptor (ER)-positive and, while targeting hormone receptors like ER is beneficial, many obese women see a recurrence of their cancer after standard chemotherapy regimens. Breast tumors also highly express AHR, which has made AHR targeting compounds (both agonists and antagonists) the subject of intense research in breast cancer models over the last decade. Our laboratory has uncovered several novel aspects of AHR signaling in response to cytokines, growth factors, and environmental toxicants, specifically the prototypical AHR agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) which underlie its role in tumorigenesis and tumor progression. We found that silencing AHR expression in breast tumor cells can block the growth response to adipokines (adipocyte-secreted factors), which are secreted into the breast tumor microenvironment by adipocytes. We have also shown AHR recruitment to the cyclin D1 (CCND1) gene promoter to increase the expression of this important oncogene involved in cell cycle progression upon insulin-like growth factor (IGF)-2 stimulus. AHR was also found to be necessary for basal and tumor necrosis factor (TNF) induced expression of superoxide dismutase 2 (SOD2), which encodes manganese superoxide dismutase (MnSOD), a crucial protein in the oxidative stress pathway. Finally, we have shown AHR is needed for the expression of solute carrier family 7 (amino acid transporter light chain, L system) member 5 (SLC7A5), which encodes L-type amino acid transporter 1 (LAT1) in breast tumor cells. The findings presented in this dissertation suggest targeting the AHR with antagonists to treat breast cancer would be the most beneficial strategy, as AHR has been implicated in several aspects of tumor initiation and progression.

Subject(s)

Breast -- Cancer -- Research.

Cancer -- Endocrine aspects.

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