A novel combinatorial approach using sulforaphane- and withaferin A-rich extracts for prevention of estrogen receptor-negative breast cancer through epigenetic and gut microbial mechanisms.

Estrogen receptor-negative [ER(-)] mammary cancer is the most aggressive type of breast cancer (BC) with higher rate of metastasis and recurrence. In recent years, dietary prevention of BC with epigenetically active phytochemicals has received increased attention due to its feasibility, effectiveness, and ease of implementation. In this regard, combinatorial phytochemical intervention enables more efficacious BC inhibition by simultaneously targeting multiple tumorigenic pathways. We, therefore, focused on investigation of the effect of sulforaphane (SFN)-rich broccoli sprouts (BSp) and withaferin A (WA)-rich Ashwagandha (Ash) combination on BC prevention in estrogen receptor-negative [ER(-)] mammary cancer using transgenic mice. Our results indicated that combinatorial BSp + Ash treatment significantly reduced tumor incidence and tumor growth (~ 75%) as well as delayed (~ 21%) tumor latency when compared to the control treatment and combinatorial BSp + Ash treatment was statistically more effective in suppressing BC compared to single BSp or Ash intervention. At the molecular level, the BSp and Ash combination upregulated tumor suppressors (p53, p57) along with apoptosis associated proteins (BAX, PUMA) and BAX:BCL-2 ratio. Furthermore, our result indicated an expressional decline of epigenetic machinery HDAC1 and DNMT3A in mammary tumor tissue because of combinatorial treatment. Interestingly, we have reported multiple synergistic interactions between BSp and Ash that have impacted both tumor phenotype and molecular expression due to combinatorial BSp and Ash treatment. Our RNA-seq analysis results also demonstrated a transcriptome-wide expressional reshuffling of genes associated with multiple cell-signaling pathways, transcription factor activity and epigenetic regulations due to combined BSp and Ash administration. In addition, we discovered an alteration of gut microbial composition change because of combinatorial treatment. Overall, combinatorial BSp and Ash supplementation can prevent ER(-) BC through enhanced tumor suppression, apoptosis induction and transcriptome-wide reshuffling of gene expression possibly influencing multiple cell signaling pathways, epigenetic regulation and reshaping gut microbiota.

Molecular, Cellular, and Technical Aspects of Breast Cancer Cell Lines as a Foundational Tool in Cancer Research.

Breast cancer comprises about 30% of all new female cancers each year and is the most common malignant cancer in women in the United States. Breast cancer cell lines have been harnessed for many years as a foundation for in vitro analytic studies to understand the use of cancer prevention and therapy. There has yet to be a compilation of works to analyze the pitfalls, novel discoveries, and essential techniques for breast cancer cell line studies in a scientific context. In this article, we review the history of breast cancer cell lines and their origins, as well as analyze the molecular pathways that pharmaceutical drugs apply to breast cancer cell lines in vitro and in vivo. Controversies regarding the origins of certain breast cancer cell lines, the benefits of utilizing Patient-Derived Xenograft (PDX) versus Cell-Derived Xenograft (CDX), and 2D versus 3D cell culturing techniques will be analyzed. Novel outcomes from epigenetic discovery with dietary compound usage are also discussed. This review is intended to create a foundational tool that will aid investigators when choosing a breast cancer cell line to use in multiple expanding areas such as epigenetic discovery, xenograft experimentation, and cancer prevention, among other areas.

Dietary Supplementation of Inulin Contributes to the Prevention of Estrogen Receptor-Negative Mammary Cancer by Alteration of Gut Microbial Communities and Epigenetic Regulations.

Breast cancer (BC) is among the most frequently diagnosed malignant cancers in women in the United States. Diet and nutrition supplementation are closely related to BC onset and progression, and inulin is commercially available as a health supplement to improve gut health. However, little is known with respect to inulin intake for BC prevention. We investigated the effect of an inulin-supplemented diet on the prevention of estrogen receptor-negative mammary carcinoma in a transgenic mouse model. Plasma short-chain fatty acids were measured, the gut microbial composition was analyzed, and the expression of proteins related to cell cycle and epigenetics-related genes was measured. Inulin supplementation greatly inhibited tumor growth and significantly delayed tumor latency. The mice that consumed inulin had a distinct microbiome and higher diversity of gut microbial composition compared to the control. The concentration of propionic acid in plasma was significantly higher in the inulin-supplemented group. The protein expression of epigenetic-modulating histone deacetylase 2 (Hdac2), Hdac8, and DNA methyltransferase 3b decreased. The protein expression of factors related to tumor cell proliferation and survival, such as Akt, phospho-PI3K, and NF-kB, also decreased with inulin administration. Furthermore, sodium propionate showed BC prevention effect in vivo through epigenetic regulations. These studies suggest that modulating microbial composition through inulin consumption may be a promising strategy for BC prevention.

Paternal Combined Botanicals Contribute to the Prevention of Estrogen Receptor-Negative Mammary Cancer in Transgenic Mice.

BACKGROUND: Parental nutritional interventions have considerably affected gametogenesis and embryogenesis, leading to the differential susceptibility of offspring to chronic diseases such as cancer. Moreover, combinatorial bioactive diets are more efficacious in ameliorating epigenetic aberrations in tumorigenesis. OBJECTIVES: We sought to investigate the transgenerational influence and epigenetic regulation of paternal sulforaphane (SFN)-rich broccoli sprouts (BSp) and epigallocatechin-3-gallate (EGCG)-rich green tea polyphenols (GTPs) consumption in the prevention of estrogen receptor-negative [ER(-)] mammary cancer in transgenic mice. METHODS: Human breast cancer cells were used to detect cell viability and epigenetic-related gene expression after treatment with EGCG and/or SFN. Twenty-four C3 or HER2/neu males were randomly assigned into 4 groups and treated with control, 26% BSp (w/w) in food, 0.5% GTPs (w/v) in drinking water or combined BSp and GTPs for 7 wk before mating. Tumor growth of nontreated female pups was monitored weekly for 19 wk (C3) and 25 wk (HER2/neu). Tumor- and epigenetic-related protein expression and enzyme activities in mammary tumors were measured. Sperms were isolated from treated males for RNA sequencing and reduced-representation bisulfite sequencing analysis. Data were analyzed with a 2-factor or 3-factor analysis of variance. RESULTS: EGCG and SFN inhibited breast cancer cell growth via epigenetic regulation. Combined BSp and GTPs synergistically (combination index < 1) suppressed tumor growth over time (P < 0.001) in 2 mouse models. Key tumor-related proteins were found differentially expressed (P < 0.05) along with epigenetic regulations in offspring mammary tumors. The transcriptome profile of sperm derived from dietary-treated males revealed differentially expressed genes correlated with spermatogenesis and breast cancer progression. DNA methylomes of the sperm and further integrated analysis with transcriptomes indicate that DNA methylation alone may not contribute to sufficient regulation in dietary-treated sperm pronucleus, leading to offspring tumor suppression. CONCLUSIONS: Collectively, paternal consumption of combined BSp and GTPs shows potential for preventing ER(-) mammary cancer through transgenerational effects. J Nutr 2023;xx:xx-xx.

Peripubertal Nutritional Prevention of Cancer-Associated Gene Expression and Phenotypes.

Breast cancer (BC) is a nearly ubiquitous malignancy that effects the lives of millions worldwide. Recently, nutritional prevention of BC has received increased attention due to its efficacy and ease of application. Chief among chemopreventive compounds are plant-based substances known as dietary phytochemicals. Sulforaphane (SFN), an epigenetically active phytochemical found in cruciferous vegetables, has shown promise in BC prevention. In addition, observational studies suggest that the life stage of phytochemical consumption may influence its anticancer properties. These life stages, called critical periods (CPs), are associated with rapid development and increased susceptibility to cellular damage. Puberty, a CP in which female breast tissue undergoes proliferation and differentiation, is of particular interest for later-life BC development. However, little is known about the importance of nutritional chemoprevention to CPs. We sought to address this by utilizing two estrogen receptor-negative [ER(-)] transgenic mouse models fed SFN-containing broccoli sprout extract during the critical period of puberty. We found that this treatment resulted in a significant decrease in tumor incidence and weight, as well as an increase in tumor latency. Further, we found significant alterations in the long-term expression of cancer-associated genes, including p21, p53, and BRCA2. Additionally, our transcriptomic analyses identified expressional changes in many cancer-associated genes, and bisulfite sequencing revealed that the antiproliferation-associated gene Erich4 was both hypomethylated and overexpressed in our experimental group. Our study indicates that dietary interventions during the CP of puberty may be important for later-life ER(-) BC prevention and highlights potential important genetic and epigenetic targets for treatment and study of the more deadly variants of BC.

Modulating Microbiota as a New Strategy for Breast Cancer Prevention and Treatment.

Breast cancer (BC) is the most common cancer in women in the United States. There has been an increasing incidence and decreasing mortality rate of BC cases over the past several decades. Many risk factors are associated with BC, such as diet, aging, personal and family history, obesity, and some environmental factors. Recent studies have shown that healthy individuals and BC patients have different microbiota composition, indicating that microbiome is a new risk factor for BC. Gut and breast microbiota alterations are associated with BC prognosis. This review will evaluate altered microbiota populations in gut, breast tissue, and milk of BC patients, as well as mechanisms of interactions between microbiota modulation and BC. Probiotics and prebiotics are commercially available dietary supplements to alleviate side-effects of cancer therapies. They also shape the population of human gut microbiome. This review evaluates novel means of modulating microbiota by nutritional treatment with probiotics and prebiotics as emerging and promising strategies for prevention and treatment of BC. The mechanistic role of probiotic and prebiotics partially depend on alterations in estrogen metabolism, systematic immune regulation, and epigenetics regulation.

Maternal soybean diet on prevention of obesity-related breast cancer through early-life gut microbiome and epigenetic regulation.

Overnutrition-induced obesity and metabolic dysregulation are considered major risk factors contributing to breast cancer. The origin of both obesity and breast cancer can retrospect to early development in human lifespan. Genistein (GE), a natural isoflavone enriched in soybean products, has been proposed to associate with a lower risk of breast cancer and various metabolic disorders. Our study aimed to determine the effects of maternal exposure to soybean dietary GE on prevention of overnutrition-induced breast cancer later in life and explore potential mechanisms in different mouse models. Our results showed that maternal dietary GE treatment improved offspring metabolic functions by significantly attenuating high-fat diet-induced body fat accumulation, lipid panel abnormalities and glucose intolerance in mice offspring. Importantly, maternal dietary GE exposure effectively delayed high-fat diet-simulated mammary tumor development in female offspring. Mechanistically, we found that maternal dietary GE may exert its chemopreventive effects through affecting essential regulatory gene expression in control of metabolism, inflammation and tumor development via, at least in part, regulation of offspring gut microbiome, bacterial metabolites and epigenetic profiles. Altogether, our findings indicate that maternal GE consumption is an effective intervention approach leading to early-life prevention of obesity-related metabolic disorders and breast cancer later in life through dynamically influencing the interplay between early-life gut microbiota, key microbial metabolite profiles and offspring epigenome.

Association of lipid profile biomarkers with breast cancer by molecular subtype: analysis of the MEND study.

There is conflicting evidence on the role of lipid biomarkers in breast cancer (BC), and no study to our knowledge has examined this association among African women. We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for the association of lipid biomarkers-total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides-with odds of BC overall and by subtype (Luminal A, Luminal B, HER2-enriched and triple-negative or TNBC) for 296 newly diagnosed BC cases and 116 healthy controls in Nigeria. Each unit standard deviation (SD) increase in triglycerides was associated with 39% increased odds of BC in fully adjusted models (aOR: 1.39; 95% CI: 1.03, 1.86). Among post-menopausal women, higher total cholesterol (aOR: 1.65; 95% CI: 1.06, 2.57), LDL cholesterol (aOR: 1.59; 95% CI: 1.04, 2.41), and triglycerides (aOR: 1.91; 95% CI: 1.21, 3.01) were associated with increased odds of BC. Additionally, each unit SD increase in LDL was associated with 64% increased odds of Luminal B BC (aOR 1.64; 95% CI: 1.06, 2.55). Clinically low HDL was associated with 2.7 times increased odds of TNBC (aOR 2.67; 95% CI: 1.10, 6.49). Among post-menopausal women, higher LDL cholesterol and triglycerides were significantly associated with increased odds of Luminal B BC and HER2 BC, respectively. In conclusion, low HDL and high LDL are associated with increased odds of TN and Luminal B BC, respectively, among African women. Future prospective studies can definitively characterize this association and inform clinical approaches targeting HDL as a BC prevention strategy.

Combinatorial epigenetic mechanisms of sulforaphane, genistein and sodium butyrate in breast cancer inhibition.

Dietary phytochemicals are currently being studied with great interest due to their ability to regulate the epigenome resulting in prevention of cancer. Some natural botanicals have been reported to have enhanced and synergistic impact on cancer suppression when administered at optimum concentrations and in-conjunction. Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables and sodium butyrate (NaB) is a short-chain fatty acid produced by gut microbiota. They have been intensively explored due to numerous anti-cancerous properties and ability to modulate epigenetic machinery by inhibition of histone deacetylase (HDAC). Genistein (GE), present in soy, is a known DNA methyltransferase (DNMT) inhibitor. While combined chemoprotective epigenetic effects induced by SFN and GE have been investigated, the key impact of combinatorial SFN-NaB, GE-NaB, and SFN-GE-NaB bioactive components in regulation of various mechanisms are poorly defined. In the present study, we found that combinations of dietary compounds had synergistic effects in decreasing cellular viability at lower dosages than their single dosages in breast cancer cell lines. The respective combinations limited growth and increased apoptosis and necrosis in cancerous cells among which the tri-combination displayed the most significant impact. Additionally, the respective combinations of compounds arrested MDA-MB-231 and MCF-7 breast cancer cells at G2/M phase. Our further mechanistic evaluation revealed that respective di-combinations and tri-combination had higher impact in down-regulation of DNMTs (DNMT3A and DNMT3B), HDACs (HDAC1, HDAC6 and HDAC11), histone methyltransferases (EZH2 and SUV39H1) and histone acetyltransferases (GCN5, PCAF, P300 and CBP) levels as compared to singly administered compounds. We also found that these combinations exhibited global epigenetic changes by inhibition of DNMT and HDAC activity, histone H3 at lysine 27 methylation (H3K27me) and histone H3 at lysine 9 methylation (H3K9me) levels, and by induction of histone acetyltransferases activity. Collectively, our investigation indicates that combined SFN, GE and NaB is highly effective in inhibiting breast cancer genesis by, at least in part, regulating epigenetic modifications, which may have implications in breast cancer therapy.

An integrated analysis of the effects of maternal broccoli sprouts exposure on transcriptome and methylome in prevention of offspring mammary cancer.

Broccoli sprouts (BSp), a cruciferous vegetable, has shown promising effects on prevention of many types of cancer including breast cancer (BC). BC has a developmental foundation, and maternal nutrition status may influence an offspring's risk to BC later in life. What is less understood, however, is the influence of maternal nutrition intervention on reversing epigenomic abnormalities that are essential in BC programming during early development. Our research focused on how maternal exposure to BSp diet prevents offspring BC and investigation of possible epigenetic mechanisms during these processes. Our results showed that maternal feeding of BSp can prevent mammary tumor development in the offspring of a transgenic mouse model. Through comprehensive integrated multi-omics studies on transcriptomic and methylomic analysis, we identified numerous target genes exhibiting significantly differential gene expression and DNA methylation patterns in the offspring mammary tumor. We discovered that maternal exposure to BSp diet can induce both gene and methylation changes in several key genes such as Avpr2, Cyp4a12b, Dpp6, Gria2, Pcdh9 and Tspan11 that are correlated with pivotal biological functions during carcinogenesis. In addition, we found an impact of maternal BSp treatment on DNA methyltransferase and histone deacetylases activity. Our study provides knowledgeable information regarding how maternal BSp diet influences key tumor-related gene expression and the epigenetic changes using a genome-wide perspective. Additionally, these findings provide mechanistic insights into the effectiveness of maternal BSp administration on the prevention of BC in the offspring later in life, which may lead to an early-life BC chemopreventive strategy that benefits the progenies' long-term health.

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

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.

Metabolic Syndrome and Risk of Breast Cancer by Molecular Subtype: Analysis of the MEND Study.

BACKGROUND: Metabolic syndrome (MetS) is characterized by a cluster of biological irregularities. The purpose of this analysis was to examine the association of MetS with BC among Nigerian women, and for the first time evaluate this association by molecular subtype. MATERIALS AND METHODS: MetS was defined as having at least 3 out of 5 of: high blood pressure (≥ 130/85 mm Hg), reduced HDL (< 50 mg/dL), elevated triglyceride (> 150 mg/dL), high waist circumference (≥ 80 cm), and prior diagnosis of diabetes or elevated fasting glucose level (≥ 100 mg/dL). Among 296 newly diagnosed BC cases and 259 healthy controls, multivariable logistic regression models were utilized to estimate adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) for the association between MetS and BC overall. Multinomial logistic regression models were used to evaluate each molecular subtype (Luminal A, Luminal B, HER2-enriched and triple-negative or TNBC). RESULTS: After adjusting for age, socio-demographic and reproductive risk factors, there was a positive association between MetS and BC (aOR: 1.84, 95% CI: 1.07, 3.16). In stratified analyses, MetS was associated with BC regardless of BMI status; however, the estimate was significant only among normal weight women (aOR: 3.85; 95% CI: 1.25, 11.90). MetS was significantly associated with TNBC subtype (aOR: 4.37, 95% CI: 1.67, 11.44); associations for other molecular subtypes were not statistically significant. CONCLUSION: MetS appears to be a robust risk factor for BC, particularly for TNBC. Public health and clinical interventions can provide substantial benefits in reducing the burden of MetS and preventing BC among Nigerian women.

L-Serine Influences Epigenetic Modifications to Improve Cognition and Behaviors in Growth Hormone-Releasing Hormone Knockout Mice.

Neurodegenerative diseases feature changes in cognition, and anxiety-like and autism-like behaviors, which are associated with epigenetic alterations such as DNA methylation and histone modifications. The amino acid L-serine has been shown to have beneficial effects on neurological symptoms. Here, we found that growth hormone-releasing hormone knockout (GHRH-KO) mice, a GH-deficiency mouse model characterized by extended lifespan and enhanced insulin sensitivity, showed a lower anxiety symptom and impairment of short-term object recognition memory and autism-like behaviors. Interestingly, L-serine administration exerted anxiolytic effects in mice and ameliorated the behavioral deficits in GHRH-KO. L-serine treatment upregulated histone epigenetic markers of H3K4me, H3K9ac, H3K14ac and H3K18ac in the hippocampus and H3K4me in the cerebral cortex in both GHRH-KO mice and wild type controls. L-serine-modulated epigenetic marker changes, in turn, were found to regulate mRNA expression of BDNF, grm3, foxp1, shank3, auts2 and marcksl1, which are involved in anxiety-, cognitive- and autism-like behaviors. Our study provides a novel insight into the beneficial effects of L-serine intervention on neuropsychological impairments.

Genome-Wide Analysis on Transcriptome and Methylome in Prevention of Mammary Tumor Induced by Early Life Combined Botanicals.

Breast cancer (BC) is the most common malignancy and the second leading cause of cancer death among women in the United States. The consumption of natural dietary components such as broccoli sprouts (BSp) and green tea polyphenols (GTPs) has demonstrated exciting potential in reducing the risk of BC through the regulation of epigenetic mechanisms. However, little is known about their impacts on reversing epigenomic aberrations that are centrally involved in the initiation and progression of BC. Previously, we have determined the efficacy of combined BSp and GTPs treatment on the inhibition of the growth of a mammary tumor in a transgenic Her2/neu mouse model. We sought to extend our previous study to identify universal biomarkers that represent common mechanistic changes among different mouse models in response to this dietary regime by including a new transgenic mouse model, C3(1)-SV40 TAg (SV40). As a result, we identified novel target genes that were differentially expressed and methylated in response to dietary botanicals when administered singly (BSp and GTPs) and in combination (BSp + GTPs) in both mouse models. We discovered more differentially expressed and methylated genes in the combination treatment group compared to the singly administered groups. Subsequently, several biological pathways related to epigenetic regulations were identified in response to the combination treatment. Furthermore, when compared to the BSp and GTPs treatment alone, the combinatorial treatment showed a more significant impact on the regulation of the epigenetic modifier activities involved in DNA methylation and histone modifications. Our study provides key insights about the impact of the combined administration of BSp and GTPs on BC using a multi-omics analysis, suggesting a combinatorial approach is more efficacious in preventing and inhibiting BC by impacting key tumor-related genes at transcriptomic and methylomic levels. Our findings could be further extrapolated as a comprehensive source for understanding the epigenetic modifications that are associated with the effects of these dietary botanicals on BC prevention.

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 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.

Impact of Stilbenes as Epigenetic Modulators of Breast Cancer Risk and Associated Biomarkers.

With the recent advancement of genetic screening for testing susceptibility to mammary oncogenesis in women, the relevance of the gene-environment interaction has become progressively apparent in the context of aberrant gene expressions. Fetal exposure to external stressors, hormones, and nutrients, along with the inherited genome, impact its traits, including cancer susceptibility. Currently, there is increasing interest in the role of epigenetic biomarkers such as genomic methylation signatures, plasma microRNAs, and alterations in cell-signaling pathways in the diagnosis and primary prevention of breast cancer, as well as its prognosis. Polyphenols like natural stilbenes have been shown to be effective in chemoprevention by exerting cytotoxic effects that can stall cell proliferation. Besides possessing antioxidant properties against the DNA-damaging effects of reactive oxygen species, stilbenes have also been observed to modulate cell-signaling pathways. With the increasing trend of early-life screening for hereditary breast cancer risks, the potency of different phytochemicals in harnessing the epigenetic biomarkers of breast cancer risk demand more investigation. This review will explore means of exploiting the abilities of stilbenes in altering the underlying factors that influence breast cancer risk, as well as the appearance of associated biomarkers.

Association of body composition with odds of breast cancer by molecular subtype: analysis of the Mechanisms for Established and Novel Risk Factors for Breast Cancer in Nigerian Women (MEND) study.

BACKGROUND: The association between obesity and breast cancer (BC) has been extensively studied among US, European and Asian study populations, with often conflicting evidence. However, despite the increasing prevalence of obesity and associated conditions in Africa, the continent with the highest age-standardized BC mortality rate globally, few studies have evaluated this association, and none has examined in relation to molecular subtypes among African women. The current analysis examines the association between body composition, defined by body mass index (BMI), height, and weight, and BC by molecular subtype among African women. METHODS: We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for the association between measures of body composition and BC and molecular subtypes among 419 histologically confirmed cases of BC and 286 healthy controls from the Mechanisms for Established and Novel Risk Factors for Breast Cancer in Women of Nigerian Descent (MEND) case-control study. RESULTS: Higher BMI (aOR: 0.79; 95% CI: 0.67, 0.95) and weight (aOR: 0.83; 95% CI: 0.69, 0.98) were associated with reduced odds of BC in adjusted models, while height was associated with non-statistically significant increased odds of BC (aOR: 1.07, 95% CI: 0.90, 1.28). In pre/peri-menopausal, but not post-menopausal women, both higher BMI and weight were significantly associated with reduced odds of BC. Further, higher BMI was associated with reduced odds of Luminal A, Luminal B, and HER2-enriched BC among pre/peri-menopausal women, and reduced odds of triple-negative BC among post-menopausal women. CONCLUSIONS: Higher BMI and weight were associated with reduced odds of BC overall and by molecular subtype among West African women. Larger studies of women of African descent are needed to definitively characterize these associations and inform cancer prevention strategies.

Association of Life-Course Educational Attainment and Breast Cancer Grade in the MEND Study.

Background: Nigeria reports the highest age-standardized mortality rate for breast cancer (BC) among African countries and disproportionately high rates of high-grade cancer. Histological grade is a strong predictor of mortality, and evidence suggests that educational attainment influences cancer outcomes. Objective: We characterize the association between educational trends across the life-course and BC grade at diagnosis. Methods: Data on 224 BC patients enrolled in the Mechanisms for Established and Novel Risk Factors for Breast Cancer in Nigerian Women (MEND) study was analyzed. Participant and parental (mother and father) education was categorized as low (primary school or less) or high (secondary school or greater). Accordingly, the educational trend across the life-course was determined for each participant relative to each parent: stable high, increasing, decreasing, or stable low. BC grade was classified as high (grade 3) or low (grades 1-2). Findings: About 34% of participants, 71% of fathers, and 85% of mothers had low education. Approximately one-third of participants were diagnosed with high-grade BC. Participants with low-grade BC were more likely to have highly educated fathers (p = 0.04). After adjusting for age, comorbidities, marital status and mammogram screening, participants with highly educated fathers were 60% less likely to have high-grade BC (aOR 0.41; 95% CI 0.20 to 0.84) compared to those with less-educated fathers. Stable high life-course education relative to father was also associated with a significantly lower likelihood of having high-grade BC (aOR 0.36; 95% CI 0.15 to 0.87) compared to stable low life-course education. No significant associations were observed for the participant's education, mother's education, or life-course education relative to mother. Conclusions: Early-life socioeconomic status (SES) may influence BC grade. This deserves further study to inform policies that may be useful in reducing high-grade BC in Nigeria.

Association of high-sensitivity C-reactive protein and odds of breast cancer by molecular subtype: analysis of the MEND study.

Breast cancer (BC) in Nigeria is characterized by disproportionately aggressive molecular subtypes. C-reactive protein (CRP) is associated with risk and aggressiveness for several types of cancer. We examined the association of high-sensitivity CRP (hsCRP) with odds of BC by molecular subtype among Nigerian women. Among 296 newly diagnosed BC cases and 259 healthy controls, multivariable logistic regression models were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the association between hsCRP and odds of BC overall and by molecular subtype (luminal A, luminal B, HER2-enriched and triple-negative or TNBC). High hsCRP (> 3 mg/L) was observed in 57% of cases and 31% of controls and was associated with 4 times the odds of BC (aOR: 4.43; 95% CI: 2.56, 7.66) after adjusting for socio-demographic, reproductive, and clinical variables. This association persisted regardless of menopausal status and body mass index (BMI) category. High hsCRP was associated with increased odds of TNBC (aOR: 3.32; 95% CI: 1.07, 10.35), luminal A BC (aOR: 4.03; 95% CI: 1.29, 12.64), and HER2-enriched BC (aOR: 6.27; 95% CI: 1.69, 23.25). Future studies are necessary in this population to further evaluate a potential role for CRP as a predictive biomarker for BC.

Systematic integrated analyses of methylomic and transcriptomic impacts of early combined botanicals on estrogen receptor-negative mammary cancer.

Dietary botanicals such as the cruciferous vegetable broccoli sprouts (BSp) as well as green tea polyphenols (GTPs) have shown exciting potential in preventing or delaying breast cancer (BC). However, little is known about their impact on epigenomic aberrations that are centrally involved in the initiation and progression of estrogen receptor-negative [ER(-)] BC. We have investigated the efficacy of combined BSp and GTPs diets on mammary tumor inhibition in transgenic Her2/neu mice that were administered the diets from prepubescence until adulthood. Herein, we present an integrated DNA methylome and transcriptome analyses for defining the early-life epigenetic impacts of combined BSp and GTPs on mammary tumors and our results indicate that a combinatorial administration of BSp and GTPs have a stronger impact at both transcriptome and methylome levels in comparison to BSp or GTPs administered alone. We also demonstrated a streamlined approach by performing an extensive preprocessing, quality assessment and downstream analyses on the genomic dataset. Our identification of differentially methylated regions in response to dietary botanicals administered during early-life will allow us to identify key genes and facilitate implementation of the subsequent downstream functional analyses on a genomic scale and various epigenetic modifications that are crucial in preventing ER(-) mammary cancer. Furthermore, our realtime PCR results were also found to be consistent with our genome-wide analysis results. These results could be exploited as a comprehensive resource for understanding understudied genes and their associated epigenetic modifications in response to these dietary botanicals.