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

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.

Potential of Dietary HDAC2i in Breast Cancer Patients Receiving PD-1/PD-L1 Inhibitors

“…GE has been reported to act as a potent chemo-preventive and therapeutic agent against various types of cancers including breast, prostate, and lung cancer [ 85 ]. For instance, GE suppresses the growth of BC cells in patient-derived tumor xenograft (PDX) [ 85 ]. Moreover, GE has been reported to modify the expression levels and activities of key epigenetic-associated genes, including HDAC2, DNA methyltransferases (DNMT3b) and ten-eleven translocation (TET3) methylcytosine dioxygenases.…”

“…Moreover, GE has been reported to modify the expression levels and activities of key epigenetic-associated genes, including HDAC2, DNA methyltransferases (DNMT3b) and ten-eleven translocation (TET3) methylcytosine dioxygenases. These genes are involved in epigenetic modifications, such as DNA methylation and histone methylation, which can regulate gene expression and impact cellular behavior [ 85 ]. By modulating the activities of these epigenetic regulators, GE may influence the epigenetic landscape of breast cancer cells, leading to changes in gene expression patterns that can affect cancer-related pathways.…”

TET Enzymes and 5hmC Levels in Carcinogenesis and Progression of Breast Cancer: Potential Therapeutic Targets

“…Finally, Genistein, a bioactive isoflavone present mainly in soybean products, decreases the TET2 and TET3 expression and delays TNBC tumor growth in vivo [ 101 ].…”

Plants as a Source of Anticancer Agents: From Bench to Bedside

“…Genistein induces Cd74 downregulation, which regulates the NF-κB/Bcl-xL/TAp63 signaling pathway by contributing to its therapeutic effect on triple-negative breast cancer (TNBC) tumors. Additionally, genistein 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 [ 289 ].…”