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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 11 3965-3972
Copyright © 1998 by The Endocrine Society

Original Studies

Selective Expression of Estrogen Receptor {alpha} and ß Isoforms in Human Pituitary Tumors1

Margaret A. Shupnik, Leslie K. Pitt, Ann Y. Soh, Alice Anderson, M. Beatrice Lopes and Edward R. Laws, Jr.

Division of Endocrinology and Metabolism, Department of Internal Medicine (M.A.S., L.K.P., A.Y.S., A.A.); Department of Neuropathology (M.B.L.); and Department of Neurosurgery (E.R.L.), University of Virginia Health Science Center, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Margaret A. Shupnik, Ph.D., Box 578 HSC, University of Virginia, Charlottesville, Virginia 22908. E-mail: mas3x{at}virginia.edu

The physiological effects of estrogen on the pituitary, including cellular proliferation and regulation of hormone synthesis, are mediated by the nuclear estrogen receptor (ER). The ER acts as a dimer to modulate gene transcription and contains specific functional domains encoded in different exons. Two separate, but related, forms of the receptor (ER{alpha} and ERß) exist, with distinct tissue and cell patterns of expression. Additional ER isoforms, generated by alternative messenger ribonucleic acid (mRNA) exon splicing, have been defined in several tissues and are postulated to play a role in tumorigenesis or in modulating the estrogen response. We examined 71 human pituitary adenomas of varying phenotypes and 6 normal pituitary specimens for ER mRNA forms by RT-PCR and hybridization blotting analysis. All prolactinomas (n = 14) contained ER{alpha}, and several contained ERß (5 of 14) mRNA. In comparison, 6 tumors that expressed PRL and GH expressed ERß (4 of 6) more frequently than ER{alpha} (3 of 6). ERß mRNA was also found more frequently in null cell (8 of 24 ER{alpha} and 14 of 24 ERß) and gonadotrope (13 of 21 ER{alpha} and 18 of 21 ERß) tumors. Additionally, ERß was found in 4 of 6 tumors that contained only GH, although ER{alpha} was not observed in this tumor type. Expression of the two ER forms within a tumor type was overlapping, but some tumors contained only 1 isoform. Expression of ER{alpha} mRNA splice variants also varied with cell type. All normal pituitaries contained ER{alpha} deletions of exon 4, 5, and 7, whereas only 2 of 6 samples contained the exon 2 deletion variant. Although the same ER{alpha} mRNA variants were observed among the various tumor types, the proportion of specific splice variants expressed varied. For example, most ER-positive prolactinomas expressed ER{alpha} variants with deletions of exon 2, 4, or 5, whereas gonadotropin tumors preferentially expressed the ER{alpha} exon 7 deletion variant. A novel ERß mRNA splice variant, missing exon 2, was observed in a majority of all ERß-positive tumors. Immunoblotting analysis of ER{alpha} and ERß proteins supported the mRNA results. Because ER{alpha} and ERß have different biological responses to selective ER modulators, and the ER deletion variants have biological effects distinct from those of the full-length ER, expression of these isoforms may influence the biological properties of these tumors and affect their ability to respond to estrogen and antiestrogen therapies.




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