The estrogen receptor beta agonist diarylpropionitrile (DPN) inhibits medulloblastoma development via anti-proliferative and pro-apototic pathways
Introduction
Among the embryonal tumors, cerebellar medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for 20–30% of intracranial tumors seen in this population. It is rare in adults, representing only 0.4–1% of CNS tumors [1]. Gender-related differences in the development of MB have been reported, with a higher incidence in males (slightly above 60%) than in females [1], [2], [3]. Besides this different susceptibility, female gender is also a significantly favorable prognostic factor in MB, with girls having a much better outcome [4], [5], [6].
Ptch1 knockout mice are one of the most powerful and widely studied models of medulloblastoma [7], [8], [9]. In this mouse model, we recently showed that susceptibility to MB development is significantly increased in ovariectomized females, and restored to levels observed in controls after estrogen replacement [10]. These findings strongly support a protective role of female sex hormones against MB, in keeping with the clear gender differences in MB incidence and prognosis observed in both children and adults. Moreover, we also reported that ERβ, but not ERα, may be involved in the modulation of MB development by estrogens. Nevertheless, the biological mechanisms behind these effects are still to be explored.
In recent years, the research on ERα and ERβ-specific agonists has provided many pharmacological tools to study the role of individual ER isoforms in cell growth regulation. 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) is an ERα-specific agonist that displays a roughly 400-fold selectivity for ERα as compared with ERβ, and has no effects on ERβ-mediated transcriptional activity [11]. 2,3-Bis (4-hydroxyphenyl)-propionitrile (DPN) is an ERβ selective agonist that displays an approximately 80-fold higher selectivity for ERβ than for ERα, and its relative potency in transcriptional assays is 170-fold greater for ERβ than for ERα [12]. Both agonists are being extensively used in immunology, physiology, and neuroscience research.
Here, we report results of an experimental study designed to examine the effects of DPN and PPT on MB preneoplastic lesions (PNLs) development, demonstrating a significant inhibitory activity of the selective ERβ agonist. We also investigated the molecular aspects responsible for the protective effect observed.
Section snippets
Mice
Mice lacking one Ptch1 allele (Ptch1+/−) [13] derived by gene targeting of 129/Sv ES cells (CD1 background) were genotyped as described [14]. Mice were housed under conventional conditions with food/water available ad libitum and 12-h light cycle. Care of experimental animals was in accordance with the Italian legislation on animal experimentation, and experimental protocols were reviewed by the Institutional Animal Care and Use Committee.
MB PNL development
To accelerate PNL development [15], all Ptch1+/− females
Effect of selective estrogen receptors agonists on incidence of MB PNLs
To assess the effect of selective estrogen-receptors agonists on development of MB PNLs, we performed ovariectomy at 4 weeks of age on neonatally irradiated Ptch1+/− females, in which MB develops early and at high incidence. Treatment with DPN – a highly potent ERβ agonist – and with PPT – a strong ERα agonist – started 1 week after ovariectomy. In parallel, a group of mice was treated with 17β-estradiol (OVX + E2). At 8 weeks of age, cerebella were histologically examined to establish the presence
Discussion
Results from the present study confirm and extend our previous data on the protective role of estrogens against MB development [10]. Here, we confirm that the inhibitory effect on tumor growth exerted by estrogens is mediated specifically via the ERβ pathway. In fact, the ERβ selective agonist DPN significantly reduced PNL incidence, an effect not elicited by the ERα selective agonist, PPT. The observation that ERβ immunoreactivity was always present in MB preneoplastic lesions, while ERα was
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
This work was supported by Grant 10357 from the Associazione Italiana Ricerca sul Cancro (AIRC).
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