High expression of estrogen receptor alpha and aromatase in glial tumor cells is associated with gender-independent survival benefits in glioblastoma patients

Abstract

Introduction Glioblastoma multiforme (GBM) is a highly malignant glial tumor, affecting men more often than women. The reason for this gender-specific predominance remains unclear, raising the question whether these effects are subject to hormonal control. The purpose of this study was to examine the expression of estrogen receptor alpha (ERα) and aromatase in human GBM tissue samples in relation to patient survival and furthermore to investigate the effect of standard chemotherapy in combination with estradiol treatment on glioblastoma tumor cell lines in vitro. Methods 60 tissue samples (31 male, 29 female) of GBM patients were analysed with immunohistochemistry for ERα and aromatase for survival analyses. The cell lines LN18 and LN229 were treated with 17β-estradiol (E2) in different dosing regimens and the cell viability was measured with MTT assay. After estradiol pre-treatment Temozolomide was added and tested again. Results High expression of ERα and aromatase in the GBM tissue samples was associated with significantly longer survival times of GBM patients, regardless of gender and body-mass-index. The treatment with high concentrations of estradiol resulted in lower tumor cell viability, compared to control. The cells significantly showed a stronger sensitivity against Temozolomid (TMZ) after estradiol pre-treatment. Conclusion ERα-expression of glial tumour cells seems to play an important prognostic role as a biomarker in GBM, as well as the expression of the enzyme Aromatase. The combined treatment of GBM with standard chemotherapy and estradiol may be beneficial to patient's survival.

Insights into the role of estrogens and androgens in glial tumorigenesis

“…[ 42 ] In agreement with this, a recent study showed that estradiol (at high concentrations) decreased cell viability and increased sensitivity to TMZ. [ 43 ] Conversely, few in vitro studies have also shown the opposite effect of estradiol. At low concentrations, estradiol increased proliferation and mitochondrial fitness of U87 cells.…”

“…One study showed that ERα is absent in T98G, U87, LN229, U138, MO59J, MO59K;[ 48 ] whereas, other studies show that ERα is expressed in U373 and D54,[ 23 ] and also in LN229, LN18, U251, U87, T98G cell lines. [ 43 47 ] These differences may have arisen due to the technique/molecule (mRNA/protein) being tested and/or differences in antibodies used/passage number of the cells.…”

Novel Insights into the Antagonistic Effects of Losartan against Angiotensin II/AGTR1 Signaling in Glioblastoma Cells

“…We may reasonably explain the latter finding with the fact that intratumoral estradiol concentrations down-regulate the expression of estrogen receptor-α in terms of mRNA and protein content as a classical biological feature of the occurred estrogen receptor-α wild type functional transactivation [ 33 , 34 ]. The data of Jiménez research work [ 13 ] appeared to not fit with those of Honikl and coworkers [ 35 ], who reported how in 60 glioblastoma patients, the increase of aromatase is concomitant with a longer survival even though the intratumoral estradiol concentrations are not documented. In addition, the latter study reported how the administration of estrogen at supraphysiological doses ranging from 10 to 50 µM dramatically reduced glioblastoma cell viability.…”

The role of sex genotype in paediatric CNS tumour incidence and survival

“…The higher incidence of gliomas in male patients when compared with their premenopausal female counterparts has been attributed to the protective effects of oestrogen. The discovery of oestrogen receptors and aromatase enzymes which converts testosterone to oestradiol in certain gliomas further supports the significant influence of sex hormones in tumour cell proliferation and death [ 21 , 22 ].…”