Expression of a Subset of Steroid Receptor Cofactors Is Associated with Progesterone Receptor Expression in Meningiomas 1 Rona S. Carroll, 2 Myles Brown, Jianping Zhang, James DiRenzo, Jaime Font De Mora, and Peter McL. Black Neurosurgical Laboratories, Brigham and Women’s Hospital, Brain Tumor Center, Brigham and Women’s Hospital, The Children’s Hospital, and Dana Farber Cancer Institute, Department of Surgery, Harvard Medical School [R. S. C., J. Z., P. M. B.], and Department of Medicine, Brigham and Women’s Hospital, and Department of Adult Oncology, Dana-Farber Cancer Institute [M. B., J. D., J. F. D.], Boston, Massachusetts 02115 ABSTRACT The predominance of meningiomas in females, their accelerated growth during the luteal phase of the menstrual cycle and during pregnancy, and the association between meningiomas and breast cancer have led to a number of studies examining the potential role of steroids on the growth of meningiomas. There are numerous discrepancies in the literature about the mitogenic effects of steroids on meningiomas in both in vitro and in vivo models. The aim of this study was to examine the expression of three steroid receptor coactivators, along with progesterone receptor and estrogen receptor in meningiomas. This additional regula- tory layer may explain the heterogeneity of hormone re- sponses observed in these tumors. Using Western blot anal- ysis and immunohistochemistry, we demonstrate the expres- sion of the steroid coactivators steroid receptor cofactor (SRC-1), amplified in breast cancer protein (AIB1), and transcriptional intermediary factor 2 (TIF2) in 81, 76, and 76% of meningiomas, respectively. The expression of SRC-1 and TIF2 is significantly related to progesterone but not to estrogen receptor expression. In contrast, seven normal brain specimens were positive for TIF2 and SRC-1 but negative for AIB1. One leptomeningeal specimen was posi- tive for AIB1, SRC-1, and progesterone receptor. The dif- ferential expression of steroid receptor coactivators may explain the differential response of these tumors to hormo- nal therapy. INTRODUCTION Meningiomas are thought to arise from the arachnoid cells that form the arachnoid villi, and account for 18% of all primary intracranial tumors and 25% of all intraspinal tumors (1, 2). The incidence of intracranial meningiomas is twice as high in women as men and occurs at nearly a 10:1 female:male ratio in intraspinal meningiomas. In a series of 517 patients with men- ingiomas seen by the Brain Tumor Group at Brigham and Women’s Hospital, the female:male ratio was 2.4:1 (3). Men- ingiomas may grow rapidly during periods of relative hormonal excess, during the luteal phase of the menstrual cycle, and during pregnancy (4). Several investigators have reported an increase in the size of or symptoms from meningiomas in the latter trimesters of pregnancy, which resolve after childbirth (4, 5). There is also an association between meningiomas and breast cancer. Three separate studies have demonstrated a positive correlation between breast cancer and meningiomas (6 – 8). Although many studies have attempted to define the role of these hormones in meningioma growth, the specific activities of these hormones in meningioma pathogenesis remain unknown. The potential role of estrogen and progesterone on the growth of meningiomas has been investigated several different ways with in vitro and in vivo models. The first set of studies focused on the expression of the receptors in meningiomas (9, 10). Sec- ondly, studies were conducted to try to assess the mitogenic effects of estrogen, progesterone agonists, and/or progesterone antagonists both on meningioma cell cultures and spheroids and on tumors implanted in vivo (11). Our laboratory demonstrated that 64% of meningiomas express mRNA for the PR and that its expression correlates with nuclear localization of the receptor by immunohistochemistry (12). Using reverse transcription and PCR Southern blot analysis, we have demonstrated the presence of mRNA for ER- 3 and - in 68 and 44% of meningiomas, respectively (13). Steroid hormone receptors belong to a large superfamily of nuclear receptors that bind DNA at specific sites to control gene transcription (14, 15). The mechanisms by which steroid recep- tors modulate the transcription of target genes are under exten- sive investigation. Once bound to ligand, the receptors undergo conformational changes and dimers of receptors recognize spe- cific regulatory DNA sequences upstream of target genes. Ac- tivated receptors, through interactions with coactivator proteins, direct the assembly and the stabilization of a preinitiation com- plex that will ultimately conduct the transcription of these genes. Recently, several coactivators that associate with these Received 12/27/99; revised 6/12/00; accepted 6/12/00. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 M. B. is supported by NIH Grants CA57374 and CA80111. R. C. is supported by the Boston Neurosurgical Foundation. 2 To whom requests for reprints should be addressed, at Brigham and Women’s Hospital, 221 Longwood Avenue, Room 121, Boston, MA 02115. Phone: (617) 278-0177; Fax: (617) 232-9029. 3 The abbreviations used are: ER, estrogen receptor; PR progesterone receptor; SRC-1, steroid receptor cofactor; TIF2, transcriptional inter- mediary factor 2; AIB1, amplified in breast cancer protein; GST, glu- tathione S-transferase; RT, room temperature; TBST, Tris-buffered sa- line [10 mM Tris (pH 8) and 0.9% NaCl] containing 0.1% Tween 20. 3570 Vol. 6, 3570 –3575, September 2000 Clinical Cancer Research Research. on November 27, 2021. © 2000 American Association for Cancer clincancerres.aacrjournals.org Downloaded from