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Tumor-Specific Expression of Alternatively Spliced Estrogen Receptor Messenger Ribonucleic Acid Variants in Human Pituitary Adenomas¹

Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dr. Sushela S Chaidarun, Neuroendocrine Unit, Bulfinch 457, Massachusetts General Hospital, Boston, Massachusetts 02114.

The well documented mitogenic and hormone regulatory effects of estrogen (E₂) on pituitary cells are mediated via its nuclear receptor (ER), a cellular homolog of v-erbA oncogene. ER isoforms generated by alternative exon splicing, termed ER variants 2ER to 7ER, have been identified in breast cancer and have been postulated to have important pathogenetic and clinical implications in tumorigenesis and/or development of hormone resistance. Because pituitary tumors, particularly prolactinomas, are known to be E₂-dependent, we investigated alternatively spliced ER variant messenger ribonucleic acid expression in 40 human pituitary tumors of various phenotypes and normal pituitary tissues, using reverse transcription-PCR and Southern blot analyses. Nine of 11 prolactinomas readily expressed multiple ER variants (2ER, 4ER, 5ER, and 7ER), whereas 6 of 11 tumors showed faint expression of 3ER. Four of 7 glycoprotein hormone-producing tumors that synthesized FSHß expressed 2ER, 5ER, and 7ER. In 9 GH- and 10 ACTH-secreting tumors examined, the expression of normal and variant ER was restricted to tumors that also exhibited scattered PRL immunoreactivity. Variant and normal ER were not found in three null cell tumors (oncocytomas) that showed negative immunoreactivity for all pituitary hormones or their subunits. In contrast, only 4ER and 7ER were uniformly detected in normal pituitaries. 6ER was not detected in any normal or neoplastic pituitary specimen studied. We conclude that multiple alternatively spliced ER variants are coexpressed with normal ER in a tumor phenotype-specific manner. In addition, ER variants 2ER and 5ER were found to be tumor specific. Future functional studies will be required to determine whether coexpression of multiple ER variants along with normal ER confers a pathophysiological role in pituitary hormone regulation and/or tumor cell proliferation.

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