title: Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk.
abstract: Pituitary tumor development involves clonal expansion stimulated by hormones and growth factorscytokines. Using mRNA differential display, we found that the bone morphogenetic protein (BMP) inhibitor noggin is down-regulated in prolactinomas from dopamine D2-receptor-deficient mice. BMP-4 is overexpressed in prolactinomas taken from dopamine D2-receptor-deficient female mice, but expression of the highly homologous BMP-2 does not differ in normal pituitary tissue and prolactinomas. BMP-4 is overexpressed in other prolactinoma models, including estradiol-induced rat prolactinomas and human prolactinomas, compared with normal tissue and other pituitary adenoma types (Western blot analysis of 48 tumors). BMP-4 stimulates, and noggin blocks, cell proliferation and the expression of c-Myc in human prolactinomas, whereas BMP-4 has no action in other human pituitary tumors. GH3 cells stably transfected with a dominant negative of Smad4 (Smad4dn; a BMP signal cotransducer) or noggin have reduced tumorigenicity in nude mice. Tumor growth recovered in vivo when the Smad4dn expression was lost, proving that BMP-4Smad4 are involved in tumor development in vivo. BMP-4 and estrogens act through overlapping intracellular signaling mechanisms on GH3 cell proliferation and c-myc expression: they had additive effects at low concentrations but not at saturating doses, and their action was inhibited by blocking either pathway with the reciprocal antagonist (i.e., BMP-4 with ICI 182780 or 17beta-estradiol with Smad4dn). Furthermore, coimmunoprecipitation studies demonstrate that under BMP-4 stimulation Smad4 and Smad1 physically interact with the estrogen receptor. This previously undescribed prolactinoma pathogenesis mechanism may participate in tumorigenicity in other cells where estrogens and the type beta transforming growth factor family have important roles.
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Paez-Pereda
authors.forename: Damiana
authors.initials: D
authors.lastname: Giacomini
authors.forename: Damian
authors.initials: D
authors.lastname: Refojo
authors.forename: Alberto Carbia
authors.initials: AC
authors.lastname: Nagashima
authors.forename: Ursula
authors.initials: U
authors.lastname: Hopfner
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Grubler
authors.forename: Alberto
authors.initials: A
authors.lastname: Chervin
authors.forename: Victoria
authors.initials: V
authors.lastname: Goldberg
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Goya
authors.forename: Shane T
authors.initials: ST
authors.lastname: Hentges
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Low
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.forename: Gunter K
authors.initials: GK
authors.lastname: Stalla
authors.forename: Eduardo
authors.initials: E
authors.lastname: Arzt
mesh_terms: D000818:Animals; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000502:physiology*; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010911:Pituitary Neoplasms / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D015175:Prolactinoma / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051901:Smad4 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
chemical_list: C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; C525811:Bmp4 protein, rat; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D004967:Estrogens; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D011960:Receptors, Estrogen; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C490811:Smad4 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors