title: Dual action of high estradiol doses on MNU-induced prostate neoplasms in a rodent model with high serum testosterone: Protective effect and emergence of unstable epithelial microenvironment.
abstract: BACKGROUND
  Estrogens are critical players in prostate growth and disease. Estrogen therapy has been the standard treatment for advanced prostate cancer for several decades; however, it has currently been replaced by alternative anti-androgenic therapies. Additionally, studies of its action on prostate biology, resulting from an association between carcinogens and estrogen, at different stages of life are scarce or inconclusive about its protective and beneficial role on induced-carcinogenesis. Thus, the aim of this study was to determine whether estradiol exerts a protective and/or stimulatory role on N-methyl-N-nitrosurea-induced prostate neoplasms.
  
  
  METHODS
  We adopted a rodent model that has been used to study induced-prostate carcinogenesis: the Mongolian gerbil. We investigated the occurrence of neoplasms, karyometric patterns, androgen and estrogen receptors, basal cells, and global methylation status in ventral and dorsolateral prostate tissues.
  
  
  RESULTS
  Histopathological analysis showed that estrogen was able to slow tumor growth in both lobes after prolonged treatment. However, a true neoplastic regression was observed only in the dorsolateral prostate. In addition to the protective effects against neoplastic progression, estrogen treatment resulted in an epithelium that exhibited features distinctive from a normal prostate, including increased androgen-insensitive basal cells, high androgens and estrogen receptor positivity, and changes in DNA methylation patterns.
  
  
  CONCLUSIONS
  Estrogen was able to slow tumor growth, but the epithelium exhibited features distinct from a normal prostatic epithelium, and this unstable microenvironment could trigger lesion recurrence over time.
authors.affiliation: Department of Cell Biology-Institute of Biology, State University of Campinas-UNICAMP, Campinas, São Paulo, Brazil.
authors.forename: Bianca F
authors.initials: BF
authors.lastname: Gonçalves
authors.affiliation: Department of Biology, Laboratory of Microscopy and Microanalysis, Institute of Biosciences, Humanities and Exact Sciences-IBILCE, UNESP-Sao Paulo State University, Sao Jose do Rio Preto, São Paulo, Brazil.
authors.forename: Silvana G P
authors.initials: SGP
authors.lastname: de Campos
authors.affiliation: Department of Biology, Laboratory of Microscopy and Microanalysis, Institute of Biosciences, Humanities and Exact Sciences-IBILCE, UNESP-Sao Paulo State University, Sao Jose do Rio Preto, São Paulo, Brazil.
authors.forename: Rejane M
authors.initials: RM
authors.lastname: Góes
authors.affiliation: Department of Morphology, Institute of Biosciences, UNESP-São Paulo State University, Botucatu, São Paulo, Brazil.
authors.forename: Wellerson R
authors.initials: WR
authors.lastname: Scarano
authors.affiliation: Department of Biology, Laboratory of Microscopy and Microanalysis, Institute of Biosciences, Humanities and Exact Sciences-IBILCE, UNESP-Sao Paulo State University, Sao Jose do Rio Preto, São Paulo, Brazil.
authors.forename: Sebastião R
authors.identifier: http://orcid.org/0000-0002-0970-4288
authors.initials: SR
authors.lastname: Taboga
authors.affiliation: Department of Biology, Laboratory of Microscopy and Microanalysis, Institute of Biosciences, Humanities and Exact Sciences-IBILCE, UNESP-Sao Paulo State University, Sao Jose do Rio Preto, São Paulo, Brazil.
authors.forename: Patricia S L
authors.initials: PSL
authors.lastname: Vilamaior
mesh_terms: D000728:Androgens / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D002273:Carcinogens / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D018450:Disease Progression; D004847:Epithelial Cells / Q000473:pathology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008770:Methylnitrosourea / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D011471:Prostatic Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D065840:Protective Factors; D051381:Rats
chemical_list: D000728:Androgens; D002273:Carcinogens; D004958:Estradiol; D008770:Methylnitrosourea
keywords: DNA damage/repair; cancer; exocrine glands; light microscopy; reproductive biology