Effects of Atrazine on Estrogen Receptor α- and G Protein-Coupled Receptor 30-Mediated Signaling and Proliferation in Cancer Cells and Cancer-Associated Fibroblasts.
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The pesticide atrazine does not bind or activate the classical estrogen receptor (ER), but up-regulates the aromatase activity in estrogen-sensitive tumor cells. It has recently been reported that the G protein estrogen receptor (GPR30/GPER) is involved in certain biological responses to endogenous estrogens and environmental compounds exerting estrogen-like activity.We aimed to evaluate the potential of atrazine to trigger the GPER-mediated signaling in cancer cells and cancer-associated fibroblasts (CAFs).Using gene reporter assays in diverse types of cancer cell, we found that atrazine does not transactivate endogenous ERα or chimeric proteins that encode the ERα and ERβ hormone binding domains. Conversely, atrazine was able to bind to GPER to induce ERK activation and the expression of estrogen target genes, which interestingly relied on both GPER and ERα expression. As a biological counterpart, atrazine stimulated the proliferation of ovarian cancer cells depending on GPER and ERα, as evidenced by gene silencing experiments and using specific signaling inhibitors. Of note, atrazine through GPER elicited ERK phosphorylation, gene expression and migration in CAFs, thus extending its stimulatory role to these main players of the tumor microenvironment.The current results suggest a novel mechanism through which atrazine may exert relevant biological effects in cancer cells and CAFs. On the basis of our data, atrazine should be included among the environmental contaminants that may elicit estrogenic activity through the GPER-mediated signaling.