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Bone Morphogenetic Protein and Retinoic Acid-Inducible Neural Specific Protein-3 Is Expressed in Gonadotrope Cell Pituitary Adenomas and Induces Proliferation, Migration, and Invasion

Departments of Medicine (L.S.-C., M.X., J.E., S.N.-P., M.E.W.), Pathology (B.K.K.-D.), and Neurosurgery (K.L.), University of Colorado at Denver and Health Sciences Center and Research Service, (L.S.-C., M.X., J.E., S.N.-P., M.E.W.), Veterans Affairs Medical Center, Denver, Colorado 80220; and Creative Research Initiative and Graduate School of Pharmaceutical Sciences (I.M.), Hokkaido University, Sapporo 001-0021, Japan

Address all correspondence and requests for reprints to: M. E. Wierman, 111H Endocrinology, Veterans Affairs Medical Center, 1055 Clermont Street, Denver, Colorado 80220. E-mail: margaret.wierman{at}uchsc.edu.

Pituitary tumors are common intracranial neoplasms that often result in endocrine dysfunction due to hormone overproduction or deficiencies from mass effects. Gonadotrope cell or gonadotropinomas are tumors that produce LH and/or FSH and represent 40% of macroadenomas. Little is known about their underlying pathogenic mechanisms. We compared expression profiles of 10 gonadotropinomas with nine normal pituitaries by cDNA array and identified bone morphogenetic protein- and retinoic acid-inducible neural-specific protein-3 (BRINP3) as overexpressed in tumors, compared with normals. BRINP3 is a novel, normally brain restricted protein of unknown function. BRINP3 mRNA was expressed selectively in gonadotropinomas. Subcellular localization studies showed that BRINP3 was targeted to the mitochondria, but BRINP3 overexpression was unable to protect pituitary cells against programmed cell death induced by growth factor withdrawal. However, BRINP3 overexpression in pituitary gonadotrope cells promoted proliferation, migration, and invasion. A BRINP3 antibody was raised that demonstrated clustered expression of BRINP3 protein in gonadotropinomas and not in normal human pituitary samples. Thus, BRINP3 is a mitochondrially localized protein that is selectively up-regulated in human gonadotropinomas. Its actions to increase proliferation, migration, and invasion suggest it may play an important role in pituitary tumorigenesis.