Advisor(s)
Trygve Tollefsbol
Committee Member(s)
Edwin Aroke
Greer Dolby
Liou Sun
Yuanyuan Li
School
College of Arts and Sciences
Document Type
Dissertation
Department (new version)
Biology
Date of Award
9-9-2024
Abstract
Breast cancer (BC) is global burden for the health of women. It is the most commonly diagnosed cancer in women and the second leading cause of cancer mortality among women in the United States. One in every eight women in the USA has a chance of developing invasive BC in her lifetime. The limitations of the available therapeutics for BC treatment have brought the dietary prevention of BC to the attention of the scientific community as a safe, natural, and easy to implement therapeutic strategy. In this regard, our laboratory with many other laboratories have demonstrated the anti-BC effect of bioactive phytochemicals. Previous investigations from our laboratory further demonstrated that combining multiple bioactive phytochemicals enables targeting several neoplastic signaling pathways in BC simultaneously. However, little is known about their epigenetic mechanisms, particularly when applied in combination, their impact at the chromatin level, and their applicability in translational medicine. We, therefore, focused on investigations to address these questions with bioactive compounds sulforaphane (SFN), phenethyl isothiocyanate (PEITC) and withaferin A (WA). According to our results, combining PEITC and WA resulted in a synergistic induction of cell cycle arrest, apoptosis and tumor formation efficiency reduction in MCF-7 and MDA-MB-231 BC cells. Combinatorial PEITC and WA further targeted HDAC and DNMT pathways with a subsequent alteration of the expression of proteins associated with cell cycle and apoptosis that resulted in BC inhibition. We reconstructed a dCas9-HDAC8-EGFP fusion to perform epigenetic editing. In combination with appropriate gRNAs, dCas9-HDAC8-EGFP fusion enabled transcriptional downregulation of ESR1, TERT and CDKN1C genes by specifically depleting the H3K9ac level on the recruitment loci. Interestingly, addition of histone deacetylase inhibitors including SFN neutralize the outcomes of such dCas9-HDAC8-EGFP-induced epigenetic editing. Additionally, combinatorial administration of sulforaphane (SFN)-rich broccoli sprouts (BSp) and withaferin A (WA)-rich ashwagandha (Ash) in transgenic mice resulted in significant reduction of tumor incidence and tumor growth (~75%). Findings from our molecular and transcriptome analysis further indicated that BSp and Ash combination could inhibit BC through enhanced tumor suppression and apoptosis induction as well as possibly impacting multiple cell signaling pathways, epigenetic regulation and reshaping gut microbiota.
ProQuest ID
Recommended Citation
Rahman, Mohammad Mijanur, "Investigation On The Epigenetic Mechanisms Modified By Dietary Phytochemicals In Inhibiting Mammary Cancer" (2024). All ETDs from UAB. 7611.
https://digitalcommons.library.uab.edu/etd-collection/7611
