Cancer Letters

Cancer Letters

Volume 308, Issue 2, 28 September 2011, Pages 197-202
Cancer Letters

The estrogen receptor beta agonist diarylpropionitrile (DPN) inhibits medulloblastoma development via anti-proliferative and pro-apototic pathways

https://doi.org/10.1016/j.canlet.2011.05.004Get rights and content

Abstract

Gender-related differences in medulloblastoma (MB) development have been reported with a higher incidence in males (slightly above 60%) than in females, female gender being also a significantly favorable prognostic factor in MB. The present study focused on the evaluation of the mechanisms by which estrogens protect against MB formation. To this end, we used a well characterized mouse model of MB – the Patched1 heterozygous mice. Ovariectomized mice were treated with 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), a highly potent ERβ agonist, or 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT), a highly potent ERα agonist. Our results show that the ERβ selective agonist DPN significantly inhibits development of MB preneoplastic lesions when compared with untreated ovariectomized mice, restoring the final incidence to that observed in the intact controls, and that these effects were achieved via activation of anti-proliferative and pro-apototic pathways. On the other hand, the ERα selective agonist PPT did not influence MB tumorigenesis relative to untreated ovariectomized mice.

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).

References (25)

  • M.D. Prados et al.

    Medulloblastoma in adults

    Int. J. Radiat. Oncol. Biol. Phys.

    (1995)
  • G.P. Cardona-Gómez et al.

    Interactions of estrogens and insulin-like growth factor-I in the brain: implications for neuroprotection

    Brain Res. Rev.

    (2001)
  • M.W. Kieran et al.

    Brain tumors: from childhood through adolescence into adulthood

    J. Clin. Oncol.

    (2010)
  • S. Preston-Martin et al.

    Primary tumors of the brain, cranial nerves and cranial meninges in Victoria, Australia, 1982–1990: patterns of incidence and survival

    Neuroepidemiology

    (1993)
  • CBTRUS. Statistical Report: Primary Brain Tumors in the United States, 2000–2004. The Central Brain Tumor Registry of...
  • M.D. Weil et al.

    Influence of a child’s sex on medulloblastoma outcome

    JAMA

    (1998)
  • E.K. Curran et al.

    Gender affects survival for medulloblastoma only in older children and adults: a study from the surveillance epidemiology and end results registry

    Pediatr. Blood Cancer

    (2009)
  • L.V. Goodrich et al.

    Altered neural cell fates and medulloblastoma in mouse patched mutants

    Science

    (1997)
  • R.H. Zurawel et al.

    Evidence that haploinsufficiency of Ptch leads to medulloblastoma in mice

    Genes Chromosomes Cancer

    (2000)
  • S. Pazzaglia et al.

    High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice

    Oncogene

    (2002)
  • M. Mancuso et al.

    Protective role of 17beta-estradiol on medulloblastoma development in Patched1 heterozygous mice

    Int. J. Cancer

    (2010)
  • S.R. Stauffer et al.

    Pyrazole ligands: structure–affinity/activity relationships and estrogen receptor-alpha-selective agonists

    J. Med. Chem.

    (2000)
  • Cited by (0)

    View full text