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[New mechanisms involved in the pathogenesis of pituitary adenomas]
Damiana Giacomini1, Marcelo Páez-Pereda, Damián Refojo
1Departamento de Fisiologia, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
Abstract:
We studied Smad-4dn tumors generated from lactosomatotrophic GH3 cells stably transfected with a dominant negative form of Smad-4 (a bone morphogenetic protein-4, BMP-4, signal co-transducer) which had reduced tumorigenicity in nude mice, but had showed a late increase in tumor size. We found that they had lost in vivo the expression of Smad-4dn and had recovered c-Myc expression. In accordance, BMP-4 is overexpressed and stimulates the expression of c-Myc in human prolactinomas, but not in other human pituitary adenomas or normal pituitary. In addition ICI 182,780 inhibited BMP-4 stimulated c-Myc expression and BMP-4 and 17 beta-estradiol in combination had an additive effect on GH3 cell proliferation. Their action was inhibited by blocking BMP-4 with ICI 182,780 or 17 beta-estradiol with Smad-4dn. Furthermore, co-immunoprecipitation studies demonstrate that Smad-4 physically interacts with the ER alpha/ER beta. We show for the first time the role of BMP-4 in prolactinoma pathogenesis, involving a functional cross-talk BMP-4/E2.
Insights
Bone morphogenetic protein-4 (BMP-4) is implicated in prolactinoma development, interacting with estrogen signaling. This study reveals BMP-4
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Context:
- Prolactinomas are pituitary tumors often associated with hormonal imbalances.
- The role of bone morphogenetic protein-4 (BMP-4) signaling in pituitary tumorigenesis is not fully understood.
- Previous studies indicated Smad-4 involvement in BMP signaling pathways.
Purpose:
- To investigate the role of BMP-4 in the pathogenesis of prolactinomas.
- To explore the interaction between BMP-4 signaling and estrogen signaling in pituitary tumor cells.
- To elucidate the molecular mechanisms underlying prolactinoma growth.
Summary:
- Studies utilizing Smad-4dn transfected GH3 cells showed reduced tumorigenicity but later tumor growth, with loss of Smad-4dn and recovery of c-Myc expression.
- BMP-4 is overexpressed and stimulates c-Myc expression in human prolactinomas, unlike other pituitary adenomas or normal pituitary tissue.
- BMP-4 and 17 beta-estradiol synergistically promote GH3 cell proliferation, with Smad-4 interacting with estrogen receptors (ER alpha/ER beta).
Impact:
- This research establishes BMP-4 as a key player in prolactinoma pathogenesis.
- Identifies a novel functional cross-talk between BMP-4 and estrogen signaling (E2) in prolactinomas.
- Provides potential therapeutic targets for prolactinoma treatment by modulating BMP-4 and estrogen pathways.