G-protein-coupled receptor 30 and estrogen receptor-alpha are involved in the proliferative effects induced by atrazine in ovarian cancer cells

Atrazine, one of the most common pesticide contaminants, has been shown toup-regulate aromatase activity in certain estrogen-sensitive tumors without binding or activatingthe estrogen receptor (ER). Recent investigations have demonstrated that the orphan G-protein–coupled receptor 30 (GPR30), which is structurally unrelated to the ER, mediates rapid actionsof 17!-estradiol and environmental estrogens.OBJECTIVES: Given the ability of atrazine to exert estrogen-like activity in cancer cells, we evaluatedthe potential of atrazine to signal through GPR30 in stimulating biological responses in cancer cells.METHODS AND RESULTS: Atrazine did not transactivate the endogenous ER" in different cancer cellcontexts or chimeric proteins encoding the ER" and ER! hormone-binding domain in gene reporterassays. Moreover, atrazine neither regulated the expression of ER" nor stimulated aromatase activity.Interestingly, atrazine induced extracellular signal-regulated kinase (ERK) phosphorylation and theexpression of estrogen target genes. Using specific signaling inhibitors and gene silencing, wedemonstrated that atrazine stimulated the proliferation of ovarian cancer cells through theGPR30–epidermal growth factor receptor transduction pathway and the involvement of ER".CONCLUSIONS: Our results indicate a novel mechanism through which atrazine may exert relevantbiological effects in cancer cells. On the basis of the present data, atrazine should be included amongthe environmental contaminants potentially able to signal via GPR30 in eliciting estrogenic action.