Abstract
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.
Highlights
Our results provided important evidence that GE was effective in delaying Triple-negative breast cancer (TNBC) development by induction of several tumor-associated genes and regulation of epigenetic modulations, including influencing key epigenetic-related gene expression, DNA methylation and histone methylation processes
Our results showed that there were no adverse effects on the body weight (Figure S1) and other general wellbeing parameters, suggesting the soybean GE is safe to use in NSG mice
We further investigated the potential mechanism underlying the anti-cancerous effects of GE on TNBC by exploring the Cluster of Differentiation 74 (Cd74)-regulated signal pathway
Summary
Breast cancer is the most common malignancy and leading cause of mortality among women worldwide [1]. Recent investigations have implicated the ability of GE to regulate epigenetic mechanisms that are often involved with reversing silenced expression of tumor suppressor genes, leading to cancer prevention/therapeutic effects [15]. We investigated the efficacy of bioactive dietary soybean GE treatment in preclinical TNBC PDX mouse models and the underlying impacts on epigenetic mechanisms. We investigated the effect of GE on various epigenetic-associated key gene expressions and important epigenetic enzymatic activities as well as other pivotal epigenetic processes including global DNA hydroxymethylation and histone methylation. Our results provided important evidence that GE was effective in delaying TNBC development by induction of several tumor-associated genes and regulation of epigenetic modulations, including influencing key epigenetic-related gene expression, DNA methylation and histone methylation processes
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