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Differential Expression of Estrogen Receptor-ß (ERß) in Human Pituitary Tumors: Functional Interactions with ER and a Tumor-Specific Splice Variant¹

Neuroendocrine Unit, Departments of Medicine and Neurosurgery (B.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: J. M. Alexander, Ph.D., Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Room 944, 330 Brookline Avenue, Boston, Massachusetts 02215.

The mitogenic and regulatory effects of estrogen (E₂) in adenohypophysial cells are known to be mediated through the nuclear estrogen receptor (ER). Expression of ER and several of its messenger ribonucleic acid (RNA) alternate splice variants has been shown to be restricted to prolactinomas and gonadotroph tumors. However, little is known about gene expression patterns of the novel nuclear hormone receptor ERß in the neoplastic pituitary. ERß has high homology to ER in the DNA- and ligand-binding domains, but encodes a distinct transcriptional activating function-1 (AF-1) domain. Using RT-PCR analysis of total RNA from 38 human pituitary adenomas, we found that ERß messenger RNA was coexpressed with ER and its splice variants in 60% of prolactinomas, 100% of mixed GH/PRL tumors, and 29% of gonadotroph tumors. ERß gene expression was not limited to ER-positive tumor subtypes, however, and was also found in 100% of null cell tumors, 80% of somatotroph tumors, and 60% of corticotroph tumors. Because ERß is coexpressed with ER and its splice variants in prolactinomas and gonadotroph tumors, we functionally characterized the potential interactions between ERß and ER. We also examined the potential cooperative effects on ERß-mediated gene expression of a tumor-specific truncated 5ER splice variant that has been shown to be coexpressed in the majority of ER-positive tumors. This exon 5 splice variant encodes the AF-1 domain as well as regions critical for DNA binding and nuclear localization, but lacks the ligand-binding and AF-2 domains. Mammalian expression vectors encoding ER, 5ER, and/or ERß complementary DNAs were transiently transfected along with an E₂ response element promoter-luciferase (ERELuc) reporter into human ER/ERß-negative osteosarcoma U2-OS cells. ERß was less potent than ER in activating E₂-stimulated ERELuc activity (4- vs. 14-fold relative to basal control levels). However, when 5ER was coexpressed with ERß or ER, E₂-stimulated ERELuc activity was markedly increased to 8- and 57-fold, respectively, relative to basal control levels when each full-length isoform was expressed alone. Finally, coexpression of ERß with ER did not significantly alter the E₂-stimulated ERELuc activity induced by ER alone. Cotreatment with tamoxifen markedly inhibited all E₂-stimulated ERELuc responses to baseline levels. Together, these data suggest that ERß has a minor role in mediating E₂ responses in ER-positive tumors, but may be the main mediator of E₂-stimulated gene expression when expressed alone in somatotroph, corticotroph, and null cell tumors. This low, but significant, level of ERß trans-activation potential may be enhanced by coexpression of 5ER in neoplastic pituitary. Therefore, E₂-mediated gene expression in normal and neoplastic pituitary appears to be highly dependent on the expression of ER and ERß isoforms, which have varying transcriptional activities.

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