Peripubertal Nutritional Prevention of Cancer-Associated Gene Expression and Phenotypes

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.

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

“…The Her2/neu mouse model overexpresses activated oncogene Erbb2 and spontaneously develops ERnegative mammary cancer tumors at 20 weeks with an average latency at 25 weeks [19,62]. C3(1)-TAg mouse model expresses Tag gene and spontaneously develops mammary cancer tumors resembling Ductal Carcinoma in situ (DCIS) at 15 weeks of age [63,64]. Animal models were purchased from the Jackson Laboratory (Bar Harbor, ME, USA).…”

Lifestyle Modifications and Breast Cancer Risk

“…Collectively, the manuscripts in this Special Issue highlight the multiplicity of the cellular mechanisms by which diet and exercise may influence breast cancer risk. They include: (a) alterations in body composition resulting in changes in adipokine profile [12] and possibly hormone signaling [9]; (b) influence on cellular pathways and molecular targets such as PPAR7, mTOR, and lipogenesis, which affect the balance between cell proliferation and apoptosis [7]; (c) alterations in the long-term expression of cancer-associated genes, including p21, p53, and BRCA2 (5); and (d) epigenetic regulation [5,13]. In this regard, Gillman et al [13] assessed the methylation of 11 breast-cancer-related genes at baseline, after completing 16 weeks of supervised exercise intervention and six months after the completion of the intervention in a group of 135 women.…”