title: Functional consequences of prolactin signalling in endothelial cells: a potential link with angiogenesis in pathophysiology?
abstract: Prolactin is best known as the polypeptide anterior pituitary hormone, which regulates the development of the mammary gland. However, it became clear over the last decade that prolactin contributes to a broad range of pathologies, including breast cancer. Prolactin is also involved in angiogenesis via the release of pro-angiogenic factors by leukocytes and epithelial cells. However, whether prolactin also influences endothelial cells, and whether there are functional consequences of prolactin-induced signalling in the perspective of angiogenesis, remains so far elusive. In the present study, we show that prolactin induces phosphorylation of ERK1/2 and STAT5 and induces tube formation of endothelial cells on Matrigel. These effects are blocked by a specific prolactin receptor antagonist, del1-9-G129R-hPRL. Moreover, in an in vivo model of the chorioallantoic membrane of the chicken embryo, prolactin enhances vessel density and the tortuosity of the vasculature and pillar formation, which are hallmarks of intussusceptive angiogenesis. Interestingly, while prolactin has only little effect on endothelial cell proliferation, it markedly stimulates endothelial cell migration. Again, migration was reverted by del1-9-G129R-hPRL, indicating a direct effect of prolactin on its receptor. Immunohistochemistry and spectral imaging revealed that the prolactin receptor is present in the microvasculature of human breast carcinoma tissue. Altogether, these results suggest that prolactin may directly stimulate angiogenesis, which could be one of the mechanisms by which prolactin contributes to breast cancer progression, thereby providing a potential tool for intervention.
authors: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. a.q.reuwer@amc.uva.nl
authors: Anne Q
authors: AQ
authors: Reuwer
authors: Patrycja
authors: P
authors: Nowak-Sliwinska
authors: Laurie A
authors: LA
authors: Mans
authors: Chris M
authors: CM
authors: van der Loos
authors: Jan H
authors: JH
authors: von der Thüsen
authors: Marcel Th B
authors: MT
authors: Twickler
authors: C Arnold
authors: CA
authors: Spek
authors: Vincent
authors: V
authors: Goffin
authors: Arjan W
authors: AW
authors: Griffioen
authors: Keren S
authors: KS
authors: Borensztajn
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000009:adverse effects; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D002460:Cell Line; D002642:Chick Embryo; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010766:Phosphorylation; D011388:Prolactin / Q000009:adverse effects*; D011509:Proteoglycans / Q000378:metabolism; D011981:Receptors, Prolactin / Q000037:antagonists & inhibitors / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D043925:Angiogenesis Inducing Agents; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; C402398:prolactin, Arg(129)-; C059485:matrigel; D011388:Prolactin; D003094:Collagen