Gender effect in experimental models of human medulloblastoma: does the estrogen receptor β signaling play a role?

Alessandra Ciucci,Gian Franco Zannoni,Daniele Travaglia,Anna Saran,Mariateresa Mancuso,Giovanni Scambia,Ilaria De Stefano,Riccardo Riccardi,Daniela Gallo,Daniela Meco,Javier S Castresana

doi:10.1371/journal.pone.0101623

Abstract

BackgroundThe 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.ResultsA 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.ConclusionWe provides mechanistic evidence supporting the idea that ERβ1 signaling may have pro-differentiation and tumor suppressive function in medulloblastomas.

Highlights

Once thought to be irrelevant regarding steroid hormones action, the cerebellum is recognized to be affected by these hormones, with the majority of studies focusing on the role of estrogen
Other authors have found that female gender is a significant favorable prognostic factor in MB, with girls having a much better outcome [8,9,10]. These observations clearly suggest the existence of sexually dimorphic mechanisms that broadly impact on tumorigenesis and tumor progression. In line with these epidemiological findings, using a well characterized mouse model of radiation-induced MB, we previously showed a protective action of estrogen during early stages of MB development; susceptibility to MB development was significantly increased in OVX Ptch1+/2 females, and restored to levels observed in control mice after estrogen replacement [11]
We observed a significantly lower growth of D283 Med in nude female mice compared to males, these latter showing a shift towards tumor de-differentiation

Summary

Introduction

Once thought to be irrelevant regarding steroid hormones action, the cerebellum is recognized to be affected by these hormones, with the majority of studies focusing on the role of estrogen Both ERa and ERb are expressed in the cerebellum and their expression varies with age [1]. Little is known on the specific role of androgens in cerebellum, with only limited data suggesting that androgens may have a role in cerebellar development [3] In this context, it is noteworthy that Purkinje cells express various hormone synthesizing enzymes, including the key enzyme in estradiol formation, cytochrome P450 aromatase, implying that estrogens are synthesized locally from androgens in the brain [1]. This study aimed at evaluating the impact of gender on MB tumorigenesis

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