title: The pituitary TGFβ1 system as a novel target for the treatment of resistant prolactinomas.
abstract: Prolactinomas are the most frequently observed pituitary adenomas and most of them respond well to conventional treatment with dopamine agonists (DAs). However, a subset of prolactinomas fails to respond to such therapies and is considered as DA-resistant prolactinomas (DARPs). New therapeutic approaches are necessary for these tumors. Transforming growth factor β1 (TGFβ1) is a known inhibitor of lactotroph cell proliferation and prolactin secretion, and it partly mediates dopamine inhibitory action. TGFβ1 is secreted to the extracellular matrix as an inactive latent complex, and its bioavailability is tightly regulated by different components of the TGFβ1 system including latent binding proteins, local activators (thrombospondin-1, matrix metalloproteases, integrins, among others), and TGFβ receptors. Pituitary TGFβ1 activity and the expression of different components of the TGFβ1 system are regulated by dopamine and estradiol. Prolactinomas (animal models and humans) present reduced TGFβ1 activity as well as reduced expression of several components of the TGFβ1 system. Therefore, restoration of TGFβ1 inhibitory activity represents a novel therapeutic approach to bypass dopamine action in DARPs. The aim of this review is to summarize the large literature supporting TGFβ1 important role as a local modulator of pituitary lactotroph function and to provide recent evidence of the restoration of TGFβ1 activity as an effective treatment in experimental prolactinomas.
authors.affiliation: Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas, Vuelta de Obligado 2490, 1428 Buenos Aires, ArgentinaDepartment of MedicineCedars Sinai Medical Center, Los Angeles, California 90048, USADepartment of Cell BiologyNew York University Medical Center, 550 First Avenue, New York, New York 10016, USA Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas, Vuelta de Obligado 2490, 1428 Buenos Aires, ArgentinaDepartment of MedicineCedars Sinai Medical Center, Los Angeles, California 90048, USADepartment of Cell BiologyNew York University Medical Center, 550 First Avenue, New York, New York 10016, USA.
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Recouvreux
authors.affiliation: Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas, Vuelta de Obligado 2490, 1428 Buenos Aires, ArgentinaDepartment of MedicineCedars Sinai Medical Center, Los Angeles, California 90048, USADepartment of Cell BiologyNew York University Medical Center, 550 First Avenue, New York, New York 10016, USA.
authors.forename: M Andrea
authors.initials: MA
authors.lastname: Camilletti
authors.affiliation: Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas, Vuelta de Obligado 2490, 1428 Buenos Aires, ArgentinaDepartment of MedicineCedars Sinai Medical Center, Los Angeles, California 90048, USADepartment of Cell BiologyNew York University Medical Center, 550 First Avenue, New York, New York 10016, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
authors.affiliation: Instituto de Biología y Medicina ExperimentalConsejo Nacional de Investigaciones Científicas y Técnicas, Vuelta de Obligado 2490, 1428 Buenos Aires, ArgentinaDepartment of MedicineCedars Sinai Medical Center, Los Angeles, California 90048, USADepartment of Cell BiologyNew York University Medical Center, 550 First Avenue, New York, New York 10016, USA gdiaz@ibyme.conicet.gov.ar.
authors.forename: Graciela
authors.initials: G
authors.lastname: Díaz-Torga
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004298:Dopamine / Q000502:physiology; D018491:Dopamine Agonists / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000502:physiology; D006801:Humans; D052682:Lactotrophs / Q000502:physiology; D010902:Pituitary Gland / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D011388:Prolactin / Q000037:antagonists & inhibitors / Q000378:metabolism; D015175:Prolactinoma / Q000188:drug therapy* / Q000503:physiopathology; D053773:Transforming Growth Factor beta1 / Q000187:drug effects* / Q000502:physiology*
chemical_list: D018491:Dopamine Agonists; D053773:Transforming Growth Factor beta1; D004958:Estradiol; D011388:Prolactin; D004298:Dopamine
keywords: TGFβ1; dopamine; estradiol; resistant prolactinomas