Abstract
The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression. Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES in utero at an increased risk of developing breast cancer, but this risk may extend to their daughters and granddaughters as well. It is critical, therefore, to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible.
Highlights
The idea that susceptibility to breast cancer is determined through inherited germline mutations and by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support
Findings in animal studies Since estrogens are linked to increased breast cancer risk, and since maternal DES exposure induces cancers in the offspring’s reproductive tissues, a concern rose that daughters exposed to DES might exhibit increased risk of developing breast cancer
Mammographic density reflects the number of epithelial cells, especially terminal ductal lobular units [38], and it is strongly linked to increased breast cancer risk [39]
Summary
DES exposure might have induced epigenetic changes in primordial germ cells and germ cells, and further be detectable in the somatic cells in granddaughters and great granddaughters. We are not aware of any study that has compared epigenetic changes in germ cells and the generation somatic cells in individuals exposed to DES or other endocrine disruptors in utero. Our preliminary studies in mice suggest that this is achievable in daughters by using the well-tolerated and non-toxic histone deacetylase inhibitor valproic acid and DNMT inhibitor hydralazine. Whether these compounds prevent an increase in granddaughters and great granddaughters in experimental models remains to be investigated
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