Timing of Dietary Estrogenic Exposures and Breast Cancer Risk

Abstract

The same dietary component, such as fat or phytochemicals in plant foods, can have an opposite effect on breast cancer risk if exposed in utero through a pregnant mother or at puberty. Dietary exposures during pregnancy often have similar effects on breast cancer risk among mothers and their female offspring. High fat intake and obesity are illustrative examples: excessive pregnancy weight gain that increases high birth weight is associated with increased breast cancer risk among mothers and daughters. High body weight during childhood is inversely linked to later breast cancer risk. The main reason why the age when dietary exposures occur determines their effect on breast cancer risk likely reflects the extensive programming of the mammary gland during fetal life and subsequent reprogramming at puberty and pregnancy. Programming is a series of epigenetic/transcriptional modifications in gene expression that can be influenced by changes in the hormonal environment induced, for example, by diet. Because epigenetic modifications are inherited by daughter cells, they can persist throughout life if they occur in mammary stem cells or uncommitted mammary myoepithelial or luminal progenitor cells. Our results indicate that the estrogen receptor (ER), mitogen-activated protein kinase (MAPK), and the tumor suppressors BRCA1, p53, and caveolin-1 are among the genes affected by diet-induced alterations in programming/reprogramming. Consequently, mammary gland morphology may be altered in a manner that increases or reduces susceptibility to malignant transformation, including an increase/reduction in cell proliferation, differentiation, and survival, or in the number of terminal end buds (TEBs) or pregnancy-induced mammary epithelial cells (PI-MECs) that are the sites where breast cancer is initiated. Thus, dietary exposures during pregnancy and puberty may play an important role in determining later risk by inducing epigenetic changes that modify vulnerability to breast cancer.

The role of early life genistein exposures in modifying breast cancer risk

“…However, in a transgenic mouse model prone to pregnancy-related mammary tumorigenesis (MMTV-neu mice), the PI-MECs may be the targets for neoplastic transformation (Wagner and Smith, 2005), underlining the complexity of mammary stem cells and their role in malignant transformation. Several excellent papers have been published regarding the effects of pregnancy on gene expression, and clearly some of the changes induced by pregnancy and pubertal genistein exposure are similar, such as upregulation of BRCA1 and p53 (Cabanes et al, 2004;de Assis and Hilakivi-Clarke, 2006). …”

Early life events and conditions and breast cancer risk: From epidemiology to etiology

“…Hilakivi-Clarke and her coworkers have used rodent models to explore the ways through which diet and otherwise induced epigenetic changes in target genes might lead to strategies to prevent breast cancer. 73,74 Critically important results may also emerge from a unique follow-up of women born to mothers who have taken diethylstilbestrol (DES) during their pregnancies. Two recent publications indicated that in utero DES exposure may substantially increase breast cancer risk in the offspring.…”

Effects of Maternal Exposure to Cow's Milk High or Low in Isoflavones on Carcinogen-Induced Mammary Tumorigenesis among Rat Offspring

“…This increase in risk is thought to occur due to an increase in fetal estrogenic environment caused by the maternal diet (33,34). Our study is the first to investigate the effect of maternal milk consumption during pregnancy on the offspring's risk of mammary cancer.…”