Date of Award
Joan C. Edwards School of Medicine
Type of Degree
Dr. Travis Salisbury, Committee Chairperson
Dr. Gary Rankin
Dr. Monica Valentovic
Dr. Richard Egleton
Dr. Todd Green
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that binds pollutants, therapeutic drugs and endogenous ligands. AHR is of particular interest in cancer and has been shown to play roles in both tumor progression and tumor suppression. As a result, it has received growing attention as a possible chemotherapeutic target. AHR is expressed in all breast cancer subtypes and can promote or inhibit breast cancer depending on the ligand it binds. The Notch signaling pathway is a highly conserved evolutionary pathway that plays extremely vital roles during development by regulating cell fate and differentiation. Notch signaling has increasingly attracted attention as a therapeutic target for cancer treatments and ligand-induced Notch activation has been reported to promote the progression of several cancers including breast cancer. Jagged 1 (JAG1) is a Notch receptor ligand that is overexpressed in all breast cancer subtypes, including triple negative breast cancer (TNBC). JAG1 promotes various vital functions of cancer biology including cancer stem cell maintenance, drug-resistance, epithelialmesenchymal transition (EMT), and metastasis. The regulation of JAG1 by AHR in breast cancer cells via two AHR ligands, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2-(1’Hindole-3’-carbonyl)-thiazole-4-carboxylic acid methylester (ITE), were investigated for this dissertation. TCDD is the prototype AHR ligand, and ITE is a non-toxic endogenous AHR ligand with anti-cancer activity. Our laboratory has discovered that ligand-activated AHR inhibits the expression and activity of the JAG1-Notch pathway in human breast cancer cells, which in turn decreases breast cancer cell invasion. By conducting ribonucleic acid (RNA)-sequencing and analyzing the data via Ingenuity Pathway Analysis (IPA), we identified a significant association between TCDD-regulated genes (TRGs) and cell movement. We found that silencing AHR expression by short-interfering RNA (siRNA) or antagonizing its activity with the AHR antagonist CH-223191 in breast cancer cells restored JAG1 expression, which established that ligand-activated AHR is an inhibitor of the JAG1-Notch pathway in breast cancer cells. AHR was also found to be necessary for suppressing the expression of the EMT regulator Snail, a crucial protein required for promoting cancer metastasis. Finally, we have shown that other nontoxic AHR agonists such as tranilast also decreases JAG1 expression in TNBC cells. Collectively, my work is the first to show that ITE is a tumor-suppressing AHR ligand in breast cancer cells in part because it reduces JAG1 expression. The findings presented in this dissertation suggest targeting the JAG1-Notch pathway with non-toxic AHR ligands could be a new mechanism to suppress the invasive activity of TNBC, which is a breast cancer subtype for which there are no targeting therapies.
Breast -- Cancer -- Research.
Cancer -- Endocrine aspects.
Piwarski, Sean Alan, "Exploring the Regulatory Mechanism of the Notch Ligand Receptor Jagged1 Via the Aryl Hydrocarbon Receptor in Breast Cancer" (2018). Theses, Dissertations and Capstones. 1182.