Peripubertal Nutritional Prevention of Cancer-Associated Gene Expression and Phenotypes

SIMPLE SUMMARY: Certain life stages, known as critical periods, during growth and development are thought to be important for later-life breast cancer initiation and progression. Nutritional factors, especially those found in plant-based diets, are believed to be key to the impact of these critical periods on cancer. However, there is currently little known with respect to how nutrition during critical periods can affect breast cancer. In this study we evaluated nutritional intervention during the critical period of puberty and whether it could have a significant effect on tumor phenotype, as well as underlying gene expression, protein expression and DNA methylation patterns. We found that sulforaphane-containing broccoli sprout extracts administered during the peripubertal period in mice were able to reduce tumor size and incidence while delaying latency. We also found gross changes to gene expression patterns, including many cancer-associated genes, as well as potentially important changes to methylation profiles in our treatment groups. ABSTRACT: 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.