Patients with triple-negative breast cancer (TNBC) possess tumors that lack estrogen receptor, progesterone receptor, and human growth factor receptor 2 expression. Such patients have lower survival rates than those diagnosed with other breast cancer subtypes in part, due to the scarcity of targeted therapy for TNBC. In addition to chemotherapy, patients with TNBC often consume natural remedies, which has led us and others to evaluate the ability of plant isolates to confer anticancer and chemopreventive actions. Poly-ADP ribose polymerase (PARP) is an enzyme that promotes DNA single-strand break repair. PARP inhibitor olaparib exploits DNA repair enzyme deficiency in tumors to demonstrate anticancer activity. Emerging evidence suggests an inverse relationship between PARP and aryl hydrocarbon receptor (AhR) signaling activation due to a negative feedback mechanism between these pathways. Putative AhR agonist Dibenzyl trisulfide (DTS) is derived from Petiveria alliacea, a perennial shrub that grows in tropical regions of the world. AhR agonist 3,3′- diindolylmethane (DIM), a major metabolite of indole-3-carbinol found in cruciferous vegetables confers anticancer and chemopreventive actions. This manuscript denotes an intensive investigation of the chemotherapeutic and chemopreventive actions of DTS and DIM. We previously revealed that synthetic AhR agonist 2-(4-amino-3- methylphenyl)-5-fluorobenzothiazole (5F 203) induces the expression of putative tumor suppressor cytoglobin (CYGB) in TNBC cells and xenografts. Here, we demonstrate that DTS confers potent anticancer activity in TNBC cells in a caspase-independent manner. Furthermore, DIM and 5F 203 suppress TNBC cell migration, proliferation and enhance olaparib anticancer activity in TNBC cells. Notably, 5F 203 and to a lesser extent DIM bind to the CYGB promoter and induce CYGB in an AhR-dependent fashion to mediate anticancer actions in TNBC cells. Taken together, plant isolates represent promising agents to treat refractory forms of breast cancer and a diet rich in cruciferous vegetables promotes the anticancer actions of PARP inhibitors.
School of Medicine
Carlos A. Casiano
Daisy De Leon
Susanne B. Montgomery
Doctor of Philosophy (PhD)
Year Degree Awarded
Date (Title Page)
Library of Congress/MESH Subject Headings
Triple Negative Breast Neoplasms; 3,3'-diindolylmethane; dibenzyl trisulfide
xv, 170 p.
Loma Linda University Libraries
This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.
Wooten, Jonathan V., "Phytochemical and Synthetic AHR Ligands as Novel Therapy for Refractory Breast Cancer" (2022). Loma Linda University Electronic Theses, Dissertations & Projects. 1817.
Loma Linda University Electronic Theses and Dissertations
Loma Linda University. Del E. Webb Memorial Library. University Archives