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Differential Expression of Folate Receptor in Pituitary Adenomas¹

Department of Neurosurgery and Laboratory of Molecular Neurosurgery and Biotechnology [C-O. E., N. M. O.], Division of Cancer Biology, Departments of Radiation Oncology [E. B. O., B. C., V. L. S.] and Pathology [D. J. B.], Emory University School of Medicine, Atlanta, Georgia 30322, and Vanderbilt University, School of Medicine, Nashville, Tennessee 37232 [P. R.]

Pituitary adenomas cause significant morbidity caused by compression of regional structures or the inappropriate expression of pituitary hormones. However, little is known about the molecular changes that contribute to the development of these tumors. To investigate these changes, we recently used cDNA microarray analysis to identify several genes with altered expression patterns in pituitary adenomas. The folate receptor (FR) was significantly overexpressed in clinically nonfunctional (NF) adenomas but not in functional adenomas (adrenocorticorticotropic hormone, growth hormone, and prolactin). FR is a high affinity folate transporter that is overexpressed by other tumors and could provide a growth advantage to cells that express it. Analysis of FR expression by Western blotting confirmed that FR protein was specifically overexpressed in NF tumors. The FR was capable of binding folates from measurements of [³H] folic acid binding, indicating that the overexpressed receptor was properly folded and may mediate vitamin uptake. Comparison of protein and specific [³H] folic acid binding levels in subtypes of NF adenomas suggested that the immunohistochemically negative adenomas produced more properly folded FR than adenomas that stained positively for anterior pituitary hormones. Finally, immunohistochemistry demonstrated that FR was specifically expressed in NF adenoma cells. These results demonstrate that overexpression of FR mRNA by NF pituitary adenomas results in production of properly folded FR protein, may mediate vitamin transport, and could potentially facilitate the growth of these tumors.

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