Location: Arkansas Children's Nutrition CenterTitle: Dietary targeting of tumor suppressors and oncogenes for breast cancer prevention) Author
Submitted to: Endocrine Reviews
Publication Type: Abstract only
Publication Acceptance Date: 3/15/2012
Publication Date: 6/15/2012
Citation: Simmen, R. 2012. Dietary targeting of tumor suppressors and oncogenes for breast cancer prevention [abstract]. Endocrine Reviews. 33(3_Meeting Abstracts):S49-2. Interpretive Summary:
Technical Abstract: Breast cancer is a complex disease that arises from genetic and epigenetic changes in molecules that are critical for growth control, DNA repair, apoptosis, and differentiation. The incidence of breast cancer varies worldwide, implicating diet and lifestyle disparities among the general population as also contributory to breast cancer development and progression. Diet-mediated changes in transcriptional programs that promote the early differentiation of the mammary gland may lead to reduced breast cancer risk. Our analyses of rodent models of breast cancer and mammary epithelial and stromal fibroblast cell lines have provided significant insights into the developmental context, target cells, mechanisms of actions, and nature of bioactive components for breast cancer prevention by diet. One example is the soy isoflavone genistein that targets mammary epithelial cells and neighboring stromal adipocytes via estrogen receptor (ER)-dependent and -independent mechanisms to promote mammary epithelial differentiation. We observed that the mammary basal and luminal epithelial sub-populations (termed stem-like/progenitor cells) that are able to self-renew, grow as spheroids in the absence of attachment, and seed tumors when dys-regulated, are also targeted by certain dietary factors. Genome-wide profiling of mammary epithelial and basal stem-like epithelial subpopulations as a function of diet revealed signaling pathways involved in immune response, protein and carbohydrate metabolism, growth regulation, and stem cell niche as potentially contributing to increased resistance to carcinogenic insult. The promotion of differentiation and reduction in proliferative indices of mammary epithelial cells were accompanied by increased tumor suppressors PTEN and p53 expression, enhanced E-cadherin membrane association, and attenuated-catenin nuclear localization. In stromal adipocytes, increased adipokine adiponectin secretion and higher ER-expression constitute favorable outcomes of the mammary tumor protective effects of dietary factors. Mammary tumor prevention conferred by dietary factors is dependent on developmental context, with in utero/lactational exposure via maternal diet providing an early window for nutritional targeting. Understanding the gene and cell regulatory programs directed by bioactive dietary factors in the distinct mammary cell compartments has important implications for the development of novel strategies for breast cancer prevention and treatment.