Background: Breast cancer is the most common cancer in the United States and the second leading cause of cancer death in women. One of the most important risk factors for breast cancer is the individual genetic background which is initially generated early in human life;for example, during the processes of embryogenesis and fetal development in utero. Early embryogenesis includes a series of programming processes involving extremely accurate time-controlled gene activation/silencing expression, and epigenetic control is believed to play a key role in regulating early embryonic development. Dietary components with properties in influencing epigenetic processes are believed to have effects on cancer prevention including breast cancer. The bioactive dietary components, sulforaphane (SFN), an isothiocyanate enriched in cruciferous vegetables such as broccoli sprouts (BSp), and genistein (GE) in soybean products are strong epigenetic modulators that appear to lead to prevention of breast cancer in vitro and in vivo. Our preliminary studies have shown that maternal dietary BSp or GE treatment impact breast cancer incidence later in adult life. In particular, the maternal BSp diet results in a delay of breast cancer onset, whereas a GE diet promotes breast cancer development, in the offspring of C3(1)-SV40 Tag transgenic mice that spontaneously develop breast cancer. These provocative results suggest a comprehensive mechanism may be involved in epigenetic dietary components-induced transplacental breast cancer intervention and maternal diet instruction is urgently needed that may benefit early breast cancer prevention. Despite these promising results, however, there are many gaps in our knowledge of the epigenetic mechanisms of SFN/BSp or GE in early chemoprevention of human breast cancer. Hypothesis: Our main hypothesis is that BSp or GE bioactive natural plant products impact early embryonic development by affecting epigenetic profiles resulting in different susceptibility to breast cancer later in life in the transgenic mouse models.
Specific Aims :
The specific aims of this proposal are therefore to 1) determine the temporal effects of early BSp or GE administration on spontaneous breast cancer development in the offspring of transgenic mouse models, 2) evaluate specific epigenetic-controlled key genes such as hTERT, ER? and p16INK4a in response to maternal dietary BSp or GE treatment and 3) assess the impact of maternal BSp or GE diet on epigenomic profiles including methylome and acetylome alterations as well as determination of candidate epigenetic genes in control of early breast cancer chemoprevention by this regimen. Goal and Significance of the Proposed Research: The goal of this proposal is to determine the effectiveness of maternal BSp or GE diet on early life breast cancer intervention and the potential epigenetic mechanisms. This study may lead to translational breast cancer chemopreventive potential by appropriate administration of prenatal and/or postnatal dietary supplements leading to early breast cancer prevention. Breast cancer affects hundreds of thousands of women world-wide and elucidation of its prevention through natural bioactive products will have global impact.
Public Health Relevance Statement: Breast cancer is the most common cancer in the United States and the second leading cause of cancer death in women. The long-term goal of this proposed investigation is to develop an epigenetic-based efficacious and safe strategy for prevention of breast cancer using orally-consumed dietary compounds such as soybean genistein and broccoli sprouts sulforaphane.