Abstract 2571: Paternal epigenetic regulation contributes to the prevention of estrogen receptor-negative mammary cancer with combined broccoli sprouts and green tea polyphenols consumption in transgenic mice

ABSTRACT Background Aberrations in the regulation of cell proliferation perturb cellular homeostasis and lead to malignancies in which dysregulation of the cell cycle and suppressed apoptosis are 2 common phenomena. Combinatorial nutritional approaches could be efficacious in ameliorating these aberrations. Objectives We sought to investigate the effect of dietary broccoli sprouts (BSp) and green tea polyphenol (GTP) administration on cell cycle progression and apoptosis in mammary tumors. Methods Forty female HER2/neu transgenic mice were randomly divided into 4 groups and treated with control, 26% BSp (wt:wt) in food, 0.5% GTPs (wt:vol) in drinking water, or combined BSp and GTPs from dams’ conception until their pups were killed at 29 wk of age. Pups’ tumor growth was monitored weekly for 27 wk. Tumor cell cycle– and apoptosis-related protein expression was measured. Data were analyzed with 2-factor or 3-factor (repeated-measures) ANOVA. Results Compared with the control group, BSp and/or GTPs decreased tumor incidence (P < 0.05) and combined BSp and GTPs synergistically [combination index (CIn) < 1] reduced tumor volume over time (P-time < 0.01). BSp and/or GTPs upregulated the expression of phosphatase and tension homolog, P16, and P53 (P < 0.05) and downregulated myelocytomatosis oncogene, Bmi1 polycomb ring finger oncogene, and telomerase reverse transcriptase (P < 0.05) compared with the control group. Combined BSp and GTPs synergistically (CIn < 1) downregulated the expression of cyclin B1, D1, and E1 and cyclin-dependent kinase 1, 2, and 4 (P < 0.05) compared with the control group. Moreover, combined BSp and GTPs induced apoptosis by regulating Bcl-2-associated X protein and B-cell lymphoma 2 (P < 0.05). BSp and/or GTPs also reduced the expression of DNA methyltransferase 1, 3A, and 3B and histone deacetylase 1 compared with the control group (P < 0.05). Conclusions Collectively, lifelong BSp and GTP administration can prevent estrogen receptor–negative mammary tumorigenesis through cell cycle arrest and inducing apoptosis in HER2/neu mice.

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

Scientific Reports ◽

10.1038/s41598-021-89131-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Itika Arora ◽

Yuanyuan Li ◽

Manvi Sharma ◽

Michael R. Crowley ◽

David K. Crossman ◽

...

Keyword(s):

Estrogen Receptor ◽

Early Life ◽

Mammary Cancer ◽

Epigenetic Modifications ◽

Green Tea Polyphenols ◽

Cruciferous Vegetable ◽

Exciting Potential ◽

Genomic Scale ◽

Functional Analyses ◽

Estrogen Receptor Negative

AbstractDietary 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.

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