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

Abstract

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.

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

“…The gene expression profile and histological features of mammary neoplasia in C3 mouse model resembles human basal-like triple-negative aggressive cancers 22 , 23 . Additionally, our lab has demonstrated dysregulation of multiple epigenetic pathways in C3 model which makes this mouse model suitable for studying both anti-BC and epigenetic mechanisms at the molecular level 8 , 40 . With respect to dose selection, we opted for 26% BSp because the safety and efficacy of 26% BSp diet, especially in a combinatorial scenario, has been proven in several investigations in our laboratory 8 , 9 , 41 .…”

Advances in Plants-Derived Bioactives for Cancer Treatment

“…leaf extract in human breast cancer cell lines, where there was stated a dose-dependent inhibitory activity. Park et al [ 3 ] also addressed the ability of natural compounds to selectively target genes regulated by extracellular acidosis. Among the 102 compounds evaluated in silico, bruceine D was revealed to have the highest therapeutic potential, being capable of regulating reprogrammed genes driven by acidosis while also modulating the tumor cell–TME interactions and reducing the amyloid beta precursor protein and CD44 expression, ultimately improving the overall survival of patients living with the disease [ 3 ].…”