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Maternal soybean genistein on prevention of later-life breast cancer through inherited epigenetic regulations.

ABSTRACT: Breast cancer has strong developmental origins and maternal nutrition composition may influence later-life breast cancer risk in the offspring. Our study focused on a bioactive dietary component, genistein (GE) enriched in soybean products, to investigate specific timing of maternal GE exposure that may influence preventive efficacy of GE on offspring breast cancer later in life, and to explore the potential epigenetic mechanisms. Our results indicate a time-dependent effect of maternal GE exposure on early-life breast cancer development in offspring mice. Through integrated transcriptome and methylome analyses, we identified several candidate genes showing significantly differential gene expression and DNA methylation changes. We further found maternal long-term GE treatment can induce inherited epigenetic landmark changes in a candidate tumor suppressor gene, Trp63, resulting in transcriptional activation of Trp63 and induction of the downstream target genes. Our results suggest that maternal long-term exposure to soybean GE may influence early-life epigenetic reprogramming processes, which may contribute to its temporal preventive effects on breast cancer in the offspring. This study provides important mechanistic insights into an appropriate maternal administration of soybean products on prevention of breast cancer later in offspring life.

SUBMITTER: Chen M

PROVIDER: S-EPMC9036993 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Maternal soybean genistein on prevention of later-life breast cancer through inherited epigenetic regulations.

Chen Min M Li Shizhao S Srinivasasainagendra Vinodh V Sharma Manvi M Li Zhenhai Z Tiwari Hemant H Tollefsbol Trygve O TO Li Yuanyuan Y

Carcinogenesis 20220401 3

Breast cancer has strong developmental origins and maternal nutrition composition may influence later-life breast cancer risk in the offspring. Our study focused on a bioactive dietary component, genistein (GE) enriched in soybean products, to investigate specific timing of maternal GE exposure that may influence preventive efficacy of GE on offspring breast cancer later in life, and to explore the potential epigenetic mechanisms. Our results indicate a time-dependent effect of maternal GE expos ...[more]

PMID: 35084457

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Project description:Dietary compounds that possess the properties of altering epigenetic processes are gaining popularity as targets for cancer prevention studies. These compounds when administered at optimal concentrations and especially in combination can have enhanced effects in cancer prevention or therapy. It is important to study the interaction of two or more compounds in order to assess their role in enhancing prevention. Genistein (GEN), found in soy, has been extensively studied for its role as an epigenetic modifier especially as a DNA methyltransferase (DNMT) inhibitor and sulforaphane (SFN), found in cruciferous vegetables, is known as a histone deacetylase (HDAC) inhibitor. However, very little is known about the effects of these two compounds in conjunction in breast cancer prevention or therapy. In our current study, we determined that, at certain doses, the compounds have synergistic effects in decreasing cellular viability of breast cancer cell lines. Our results indicate that the combination of GEN and SFN is much more effective than their single doses in increasing the rate of apoptosis and lowering the colony forming potential of these cells. We determined that these compounds inhibit cell cycle progression to G2 phase in MDA-MB-231 and G1 phase in MCF-7 breast cancer cell lines. Additionally, we determined that the combination is effective as an HDAC and histone methyltransferase (HMT) inhibitor. Furthermore, we demonstrated that this combination downregulates the levels of HDAC2 and HDAC3 both at the mRNA and protein levels. We also found that these compounds have the potential to downregulate KLF4 levels, which plays an important role in stem cell formation. The combination of GEN and SFN is also effective in downregulating hTERT levels, which is known to be activated when KLF4 binds to its promoter region. Our hypothesis is further strengthened by in vivo studies, where the combination is administered to transgenic mice in the form of genistein and SFN-enriched broccoli sprouts. We have demonstrated that the combination is more effective in preventing or treating mammary cancer via extending tumor latency and reducing tumor volumes/sizes than either of these dietary components administered alone. These results are consistent with our in vitro study suggesting potential preventive and therapeutic effects of this novel dietary combinatorial approach against breast cancer.

Project description:The evolution of human diets led to preferences towards polyunsaturated fatty acid (PUFA) content with ‘Western’ diets enriched in w-6 PUFA1. Mounting evidence points to w-6 PUFA excess limiting metabolic and cognitive processes that define longevity in humans2. When chosen during pregnancy, w-6 PUFA-enriched ‘Western’ diets can reprogram maternal bodily metabolism with maternal nutrient supply precipitating the body-wide imprinting of molecular and cellular adaptations at the level of long-range intercellular signaling networks in the unborn fetus2,3. Even though unfavorable neurological outcomes are amongst the most common complications of intrauterine w-6 PUFA excess3, cellular underpinnings of life-long modifications to brain architecture remain unknown. Here, we show that nutritional w-6 PUFA-derived endocannabinoids desensitize CB1 cannabinoid receptors, thus inducing epigenetic repression of transcriptional regulatory networks controlling neuronal differentiation. We found that cortical neurons lose their positional identity and axonal selectivity once exposing mouse fetuses to excess w-6 PUFAs in utero. Conversion of w-6 PUFAs into endocannabinoids disrupted the temporal precision of signaling at neuronal CB1 cannabinoid receptors, chiefly deregulating Stat3-dependent transcriptional cascades otherwise required to execute neuronal differentiation programs. Global proteomics identified the immunoglobulin family of cell adhesion molecules (IgCAMs) as direct substrates with DNA methylome analysis and ATAC-seq uncovering epigenetic reprogramming at >1,400 sites in neurons after prolonged cannabinoid exposure. We find anxiety and depression-like behavioral traits to manifest in adult offspring, which is compatible with genetic models of reduced IgCAM expression to suggest causality to cortical wiring defects4. Overall, our data uncover a regulatory mechanism whose disruption by maternal food choices could limit the offsprings’ brain function for life.

Project description:BackgroundEstrogen receptor-? (ER?)-negative breast cancer is clinically aggressive and normally does not respond to conventional estrogen target-directed therapies. The soybean isoflavone, genistein (GE), has been shown to prevent and inhibit breast cancer and recent studies have suggested that GE can enhance the anticancer capacity of an estrogen antagonist, tamoxifen (TAM), especially in ER?-positive breast cancer cells. However, the role of GE in ER?-negative breast cancer remains unknown.MethodsWe have evaluated the in vitro and in vivo epigenetic effects of GE on ER? reactivation by using MTT assay, real-time reverse transcription-polymerase chain reaction (RT-PCR) assay, western-blot assay, immunoprecipitation (ChIP) assay, immunohistochemistry and epigenetic enzymatic activity analysis. Preclinical mouse models including xenograft and spontaneous breast cancer mouse models were used to test the efficacy of GE in vivo.ResultsWe found that GE can reactivate ER? expression and this effect was synergistically enhanced when combined with a histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), in ER?-negative MDA-MB-231 breast cancer cells. GE treatment also re-sensitized ER?-dependent cellular responses to activator 17?-estradiol (E2) and antagonist TAM. Further studies revealed that GE can lead to remodeling of the chromatin structure in the ER? promoter thereby contributing to ER? reactivation. Consistently, dietary GE significantly prevented cancer development and reduced the growth of ER?-negative mouse breast tumors. Dietary GE further enhanced TAM-induced anti-cancer efficacy due at least in part to epigenetic ER? reactivation.ConclusionsOur studies suggest that soybean genistein can epigenetically restore ER? expression, which in turn increases TAM-dependent anti-estrogen therapeutic sensitivity in vitro and in vivo. The results from our studies reveal a novel therapeutic combination approach using bioactive soybean product and anti-hormone therapy in refractory ER?-negative breast cancer which will provide more effective options in breast cancer therapy.

Dataset Information

Maternal soybean genistein on prevention of later-life breast cancer through inherited epigenetic regulations.

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Maternal soybean genistein on prevention of later-life breast cancer through inherited epigenetic regulations.

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