title: Effects of atrazine on estrogen receptor α- and G protein-coupled receptor 30-mediated signaling and proliferation in cancer cells and cancer-associated fibroblasts.
abstract: BACKGROUND
  The pesticide atrazine does not bind to or activate the classical estrogen receptor (ER), but it up-regulates the aromatase activity in estrogen-sensitive tumor cells. The G protein estrogen receptor (GPR30/GPER) has been reported to be involved in certain biological responses to endogenous estrogens and environmental compounds exerting estrogen-like activity.
  
  
  OBJECTIVE
  We aimed to evaluate the potential of atrazine to trigger GPER-mediated signaling in cancer cells and cancer-associated fibroblasts (CAFs).
  
  
  RESULTS
  Using gene reporter assays in diverse types of cancer cells, we found that atrazine did 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, appeared to rely on both GPER and ERα expression. As a biological counterpart, atrazine stimulated the proliferation of ovarian cancer cells that depend on GPER and ERα, as evidenced by gene silencing experiments and the use of specific signaling inhibitors. Of note, through GPER, atrazine elicited ERK phosphorylation, gene expression, and migration in CAFs, thus extending its stimulatory role to these main players of the tumor microenvironment.
  
  
  CONCLUSIONS
  Our 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 GPER-mediated signaling.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Albanito
authors.forename: Rosamaria
authors.initials: R
authors.lastname: Lappano
authors.forename: Antonio
authors.initials: A
authors.lastname: Madeo
authors.forename: Adele
authors.initials: A
authors.lastname: Chimento
authors.forename: Eric R
authors.initials: ER
authors.lastname: Prossnitz
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Cappello
authors.forename: Vincenza
authors.initials: V
authors.lastname: Dolce
authors.forename: Sergio
authors.initials: S
authors.lastname: Abonante
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pezzi
authors.forename: Marcello
authors.initials: M
authors.lastname: Maggiolini
mesh_terms: D001280:Atrazine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047628:Estrogen Receptor alpha; D043562:Receptors, G-Protein-Coupled; D001280:Atrazine