Hypothesis: Activation of rapid signaling by environmental estrogens and epigenetic reprogramming in breast cancer

Abstract

Environmental and lifestyle factors are considered significant components of the increasing breast cancer risk in the last 50 years. Specifically, exposure to environmental endocrine disrupting compounds is correlated with cancer susceptibility in a variety of tissues. In both human and rodent models, the exposure to ubiquitous environmental estrogens during early life has been shown to disrupt normal mammary development and cause permanent adverse effects. Recent studies indicate that environmental estrogens not only have the ability to disrupt estrogen receptor (ER) signaling, but can also reprogram the epigenome by altering DNA and histone methylation through rapid, nongenomic ER actions. We have observed xenoestrogen-mediated activation of several nongenomic signaling pathways and have identified a target for epigenetic reprogramming in MCF-7 breast cancer cells. These observations, in addition to data from the literature, support the hypothesis that activation of rapid signaling by environmental estrogens can lead to epigenetic reprogramming and contribute to the progression of breast cancer.

Risks and benefits related to alimentary exposure to xenoestrogens

“…More recently, BPA exposure in early life was correlated with an altered susceptibility to tumor formation in particular sites, such as prostate and breast. This could be due to an epigenetic reprogramming of these tissues depending on the activation of a non genomic response by BPA and other EDCs (Trevino et al, 2015). BPA exposure during fetal life is currently being considered as a time bomb for prostate cancer.…”

Endocrine-disrupting chemicals and uterine fibroids

“…Liganded nuclear hormone receptors that function as transcription factors interact with DNA, producing what are termed “genomic” effects that regulate gene transcription, but are also capable of action outside the nucleus via what is termed “non-genomic signaling” (41,42). EDCs are also capable of inducing both genomic and non-genomic signaling: both BPA and DES, for example, have been shown to activate nongenomic signaling pathways through the ER (43–48).…”

Timing of Environmental Exposures as a Critical Element in Breast Cancer Risk

“…In a recent review of the potential mechanisms underlying life-long DES effects following fetal exposures (25), epigenetic alterations such as DNA methyltransferase expression changes, altered methylation of the promoter region of estrogen target genes that may control cell fate, histone modification, and silencing of specific miRNAs were identified as having potential roles in the latent effects of DES. Most of the supporting mechanistic data for DES is in rodent uterine tissue (26) or breast cancer cell lines (27), but discoveries following prenatal ethinyl estradiol exposure in rats (another synthetic estrogen; 25) may lead to new understanding of potential mechanisms of action in the mammary gland and whether or not such mechanisms are also pertinent for DES.…”