Involvement of bone morphogenetic protein 4 (BMP-4) in pituitary prolactinoma pathogenesis through a Smad/estrogen receptor crosstalk.
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.
Paez-Pereda
Marcelo
M
Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany.
Giacomini
Damiana
D
Refojo
Damian
D
Nagashima
Alberto Carbia
AC
Hopfner
Ursula
U
Grubler
Yvonne
Y
Chervin
Alberto
A
Goldberg
Victoria
V
Goya
Rodolfo
R
Hentges
Shane T
ST
Low
Malcolm J
MJ
Holsboer
Florian
F
Stalla
Gunter K
GK
Arzt
Eduardo
E
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
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