Elsevier

Steroids

Volume 65, Issues 10–11, October–November 2000, Pages 795-800
Steroids

Occurrence, regulation, and significance of progesterone receptors in human meningioma

https://doi.org/10.1016/S0039-128X(00)00193-8Get rights and content

Abstract

The abundant expression of progesterone receptors (PR) in human meningiomas is well established. It is unknown, however, how PR expression is regulated, especially since estrogen receptors (ER) are virtually absent in these tumors. At the mRNA level, ER splice variants occur in meningioma but these appear not to be involved in the apparently autonomous PR expression. In an earlier study, because other ER-inducible proteins were either not expressed at all (pS2) or were expressed at a very low level compared to their expression in breast cancer (Cathepsin-D), the authors have postulated that the autonomous PR expression in meningioma is PR promoter-related rather than ER-related and have studied PR expression in cultured meningioma cells. PR levels appeared to decrease rapidly in vitro in monolayer as well as in three dimensional spheroid cultures. Culture conditions thus are not yet sufficient for the quantitative evaluation of PR expression. To evaluate whether PR deterioration is associated with cell turnover (meningiomas grow much faster in vitro than in vivo), the relationship between expression of the apoptotic proteins Bcl-2 and Bax and PR expression was investigated. Bcl-2 expression was found to be highest in meningioma with low PR levels, and in breast cancer tissue with high PR levels. Bax expression was not related to PR expression in any of the two tissues. Given the potential benefit of antiprogestin treatment and the occurrence in meningiomas of a protein capable of binding to the estrogen-responsive element, the expression of PR in meningioma remains a fascinating phenomenon which requires further investigation.

Introduction

The abundant expression of progesterone receptors (PR) in human meningioma tumors has been established for more than a decade now. The parallel observation that, in spite of the high concentration of PR, meningiomas essentially lack estrogen receptors (ER) has presented a challenge for the same period of time. Having apparently autonomous expression of PR, meningiomas differ from the ‘classical’ ER target tissues like uterus and oviduct, in which expression of PR is regulated by estrogens through the ER.

Meningiomas are essentially benign tumors, which are usually treated by surgery. A number of these tumors, however, cannot be resected completely and recur. Alternative or second-line treatment is not readily available since meningiomas are relatively insensitive to chemotherapy and radiation.

Meningiomas have attracted attention as being possible hormone-sensitive tumors due to: their higher incidence in women than in men; the epidemiological association of meningioma and breast cancer; and the reversible aggravation of the symptoms during periods of relative progesterone excess, such as during pregnancy and in the luteal phase of the menstrual cycle.

This paper will discuss: the occurrence of steroid receptors in human meningioma; the authors attempts to unravel the regulation of PR expression in cultured cells; the effects of antiprogestins on meningioma cells; and the possible relationship of PR expression to that of the anti- and pro-apoptotic proteins Bcl-2 and Bax.

Section snippets

Occurrence of progesterone receptors in meningioma

Following the first report by Donnell et al. [1] on the presence of ER in meningioma tissue, a large number of papers have appeared dealing with this subject. Some authors reported on the occurrence of both ER and PR, whereas others established an ER-negative (ER−)/PR-positive (PR+) phenotype. The differences appeared to be caused by methodological differences, because large numbers of apparently ER+ tumors were found to be positive only by single-point binding assays and not by Scatchard plot

Alternatively spliced ER mRNA

The estrogen-independent expression of PR has led to the hypothesis that in meningioma ER forms prevail which do not bind the ligand, and hence are not detected with ligand-binding assays and immunoassays employing antibodies that recognize the hormone-binding domain of the ER; however they are still capable of binding to the estrogen responsive element (ERE) and triggering PR expression. The authors have investigated this possibility and detected, at the mRNA level, the prevalence of ER splice

Response of meningiomas to antiprogestins

Apart from its regulation, the significance of the expression of PR in meningioma presents an intriguing question. Because of the presence of PRs in meningioma and the epidemiological data linking aggravation of meningioma symptoms to periods of high progesterone availability, the use of antiprogestins for the treatment of meningiomas has been suggested. Pilot studies with a limited number of patients [17], [18], [19] and case reports [20], [21] have fostered optimism with respect to the

Conclusions

The occurrence, regulation, and significance of PR in meningioma continues to be a fascinating area. Despite the efforts made to date, a number of questions remain to be answered. The first of these is related to the identity and function of the ERE binding protein present in meningioma cytosol. In this respect, several lines of investigation seem to converge. The existence of ER mRNA variants lacking part of the sequence points to the presence of proteins translated from these, which might be

Acknowledgments

The continuous support from Prof.dr. C.A.F. Tulleken, Department of Neurosurgery, University Medical Center Utrecht, and Dr. G. Blaauw, Department of Neurosurgery, De Wever Hospital Heerlen, The Netherlands, is gratefully acknowledged.

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