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.

Keywords: Breast cancer; Environmental estrogens; Epigenetics; Histone modifiers.

Figure 1

Model of epigenetic reprogramming by xenoestrogens and breast cancer risk. Xenoestrogens activate cell-signaling pathways, including the PI3K/Akt, PKA, and MAPK pathways (among others), leading to phosphorylation of “writer”, “reader”, and “eraser” epigenetic modifier proteins. These phosphorylation events can serve to activate or inactivate the modifier proteins resulting in alteration (either addition or loss) of specific histone modifications (Mod) and epigenetic reprogramming of target genes (i.e. oncogenes and tumor suppressors) that could ultimately contribute to breast tumorigenesis.