title: Gender effect in experimental models of human medulloblastoma: does the estrogen receptor β signaling play a role?
abstract: BACKGROUND
  The male-to-female sex ratio for medulloblastoma (MB) is approximately 1.5∶1, female gender being also a favorable prognostic factor. This study aimed at evaluating the impact of gender on MB tumorigenesis.
  
  
  METHODS
  In vitro activity of 17β-estradiol (E2), DPN [2,3-bis(4-hydroxyphenyl)-propionitrile, a selective estrogen receptor β (ERβ)-agonist], PPT [4,4',4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol, a selective ERα-agonist] or DHT (5 alpha-dihydrotestosterone) was evaluated in three human MB cell lines. D283 Med cells were transplanted into athymic mice.
  
  
  RESULTS
  A significant expression of ERβ, with little or no ERα, and low AR (androgen receptor) was found in MB cell lines. The compounds tested did not affect cell proliferation. In vivo, we observed a significantly lower growth of D283 Med in nude female mice compared to males. At microscopic examination, tumors from females showed a shift towards differentiation, as evaluated by lower nestin, and higher NSE (neuron-specific enolase) and GFAP (glial fibrillary acidic protein) expression compared to males. Tumors from females also showed lower Ki67 and p53 expression. The wild-type ERβ protein (ERβ1) was lost in male tumors, while it was a permanent feature in females, and a strong negative correlation was found between Ki67 and ERβ1 expression. Conversely, tumor levels of ERβ2 and ERβ5 did not significantly differ between genders. Increased levels of cyclin-dependent kinase inhibitor p21 were observed in females, suggesting that estrogen may decrease tumor growth through blocking cell cycle progression. An inhibition of the insulin-like growth factor I (IGF-I) signaling was also evident in females.
  
  
  CONCLUSIONS
  We provides mechanistic evidence supporting the idea that ERβ1 signaling may have pro-differentiation and tumor suppressive function in medulloblastomas.
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ciucci
authors.affiliation: Division of Pediatric Oncology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Meco
authors.affiliation: Department of Radiation Physics, Università degli Studi Guglielmo Marconi, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: De Stefano
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Travaglia
authors.affiliation: Department of Histopathology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Zannoni
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.affiliation: Division of Pediatric Oncology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Riccardi
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), CR-Casaccia, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Saran
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), CR-Casaccia, Rome, Italy.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Mancuso
authors.affiliation: Department of Obstetrics and Gynecology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Gallo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D009570:Nitriles / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects; D011422:Propionates
chemical_list: D014408:Biomarkers, Tumor; D013196:Dihydrotestosterone; D004958:Estradiol; D047629:Estrogen Receptor beta; D009570:Nitriles; D010636:Phenols; D011720:Pyrazoles; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol