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Article

Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms

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Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Integrative Center for Aging Research, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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Department of Obstetrics, Gynecology & Women’s Heath, University of Missouri, Columbia, MO 65211, USA
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Department of Surgery, University of Missouri, Columbia, MO 65211, USA
*
Authors to whom correspondence should be addressed.
Academic Editors: Dina Bellizzi and Patrizia D’Aquila
Nutrients 2021, 13(11), 3944; https://doi.org/10.3390/nu13113944
Received: 7 October 2021 / Revised: 1 November 2021 / Accepted: 2 November 2021 / Published: 4 November 2021
(This article belongs to the Special Issue Effects of Dietary Interventions on DNA Methylation during Lifecycle)
Consumption of dietary natural components such as genistein (GE) found in soy-rich sources is strongly associated with a lower risk of breast cancer. However, bioactive dietary component-based therapeutic strategies are largely understudied in breast cancer treatment. Our investigation sought to elucidate the potential mechanisms linking bioactive dietary GE to its breast cancer chemotherapeutic potential in a special subtype of aggressive breast cancer—triple-negative breast cancer (TNBC)—by utilizing two preclinical patient-derived xenograft (PDX) orthotopic mouse models: BCM-3204 and TM00091. Our study revealed that administration of GE resulted in a delay of tumor growth in both PDX models. With transcriptomics analyses in TNBC tumors isolated from BCM-3204 PDXs, we found that dietary soybean GE significantly influenced multiple tumor-regulated gene expressions. Further validation assessment of six candidate differentially expressed genes (DEGs)—Cd74, Lpl, Ifi44, Fzd9, Sat1 and Wwc1—demonstrated a similar trend at gene transcriptional and protein levels as observed in RNA-sequencing results. Mechanistically, GE treatment-induced Cd74 downregulation regulated the NF-κB/Bcl-xL/TAp63 signal pathway, which may contribute to soybean GE-mediated therapeutic effects on TNBC tumors. Additionally, our findings revealed that GE can modify expression levels of key epigenetic-associated genes such as DNA methyltransferases (Dnmt3b), ten-eleven translocation (Tet3) methylcytosine dioxygenases and histone deacetyltransferase (Hdac2), and their enzymatic activities as well as genomic DNA methylation and histone methylation (H3K9) levels. Collectively, our investigation shows high significance for potential development of a novel therapeutic approach by using bioactive soybean GE for TNBC patients who have few treatment options. View Full-Text
Keywords: genistein; triple-negative breast cancer (TNBC); patient-derived xenograft (PDX); epigenetic; RNA-seq; cancer therapy genistein; triple-negative breast cancer (TNBC); patient-derived xenograft (PDX); epigenetic; RNA-seq; cancer therapy
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MDPI and ACS Style

Sharma, M.; Arora, I.; Chen, M.; Wu, H.; Crowley, M.R.; Tollefsbol, T.O.; Li, Y. Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms. Nutrients 2021, 13, 3944. https://doi.org/10.3390/nu13113944

AMA Style

Sharma M, Arora I, Chen M, Wu H, Crowley MR, Tollefsbol TO, Li Y. Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms. Nutrients. 2021; 13(11):3944. https://doi.org/10.3390/nu13113944

Chicago/Turabian Style

Sharma, Manvi, Itika Arora, Min Chen, Huixin Wu, Michael R. Crowley, Trygve O. Tollefsbol, and Yuanyuan Li. 2021. "Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms" Nutrients 13, no. 11: 3944. https://doi.org/10.3390/nu13113944

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