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

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 elu...

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Autores principales:	Manvi Sharma, Itika Arora, Min Chen, Huixin Wu, Michael R. Crowley, Trygve O. Tollefsbol, Yuanyuan Li
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	genistein triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) epigenetic RNA-seq cancer therapy Nutrition. Foods and food supply TX341-641
Acceso en línea:	https://doaj.org/article/56c87986f1564d0da6f64f3fa99de391
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spelling	oai:doaj.org-article:56c87986f1564d0da6f64f3fa99de3912021-11-25T18:35:29ZTherapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms10.3390/nu131139442072-6643https://doaj.org/article/56c87986f1564d0da6f64f3fa99de3912021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6643/13/11/3944https://doaj.org/toc/2072-6643Consumption 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)—<i>Cd74</i>, <i>Lpl</i>, <i>Ifi44</i>, <i>Fzd9</i>, <i>Sat1</i> and <i>Wwc1</i>—demonstrated a similar trend at gene transcriptional and protein levels as observed in RNA-sequencing results. Mechanistically, GE treatment-induced <i>Cd74</i> 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 (<i>Dnmt3b</i>), ten-eleven translocation (<i>Tet3</i>) methylcytosine dioxygenases and histone deacetyltransferase (<i>Hdac2</i>), 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.Manvi SharmaItika AroraMin ChenHuixin WuMichael R. CrowleyTrygve O. TollefsbolYuanyuan LiMDPI AGarticlegenisteintriple-negative breast cancer (TNBC)patient-derived xenograft (PDX)epigeneticRNA-seqcancer therapyNutrition. Foods and food supplyTX341-641ENNutrients, Vol 13, Iss 3944, p 3944 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	genistein triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) epigenetic RNA-seq cancer therapy Nutrition. Foods and food supply TX341-641
spellingShingle	genistein triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) epigenetic RNA-seq cancer therapy Nutrition. Foods and food supply TX341-641 Manvi Sharma Itika Arora Min Chen Huixin Wu Michael R. Crowley Trygve O. Tollefsbol Yuanyuan Li Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms
description	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)—<i>Cd74</i>, <i>Lpl</i>, <i>Ifi44</i>, <i>Fzd9</i>, <i>Sat1</i> and <i>Wwc1</i>—demonstrated a similar trend at gene transcriptional and protein levels as observed in RNA-sequencing results. Mechanistically, GE treatment-induced <i>Cd74</i> 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 (<i>Dnmt3b</i>), ten-eleven translocation (<i>Tet3</i>) methylcytosine dioxygenases and histone deacetyltransferase (<i>Hdac2</i>), 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.
format	article
author	Manvi Sharma Itika Arora Min Chen Huixin Wu Michael R. Crowley Trygve O. Tollefsbol Yuanyuan Li
author_facet	Manvi Sharma Itika Arora Min Chen Huixin Wu Michael R. Crowley Trygve O. Tollefsbol Yuanyuan Li
author_sort	Manvi Sharma
title	Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms
title_short	Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms
title_full	Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms
title_fullStr	Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms
title_full_unstemmed	Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms
title_sort	therapeutic effects of dietary soybean genistein on triple-negative breast cancer via regulation of epigenetic mechanisms
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/56c87986f1564d0da6f64f3fa99de391
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Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms

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