Pituitary tumorigenesis in prolactin gene-disrupted mice.
Targeted disruption [knockout (KO)] of the mouse prolactin (PRL) gene created an animal model of primary isolated PRL deficiency in which there is no detectable PRL bioactivity. Pituitary glands of young adult female PRLKO mice were hyperplastic, and many cells had expanded cytoplasms with granular accumulations of an N-terminal peptide encoded by the disrupted PRL gene (KO/10 peptide). Confocal imaging showed that the pituitaries in PRL(+/+) and PRL(+/-) females contained dense accumulations of apparently Golgi-associated immunoreactive PRL. PRLKO female mice (15-18 months old) developed hyperemic pituitary adenomas. The pituitary tumors in PRLKO mice synthesized the KO/10 peptide, which implies that the tumors arise from the lactotroph lineage. Anchorage-independent growth was observed among pituitary cells from PRLKO mice, aged 8 months or older, but not in cells from 3-month-old PRLKO mice. GH cells appeared to be normal in PRLKO pituitaries, but were displaced by the hyperplastic and hypertrophic growth of KO/10-positive cells. Bromocriptine suppressed mean pituitary weight in 8-month-old PRLKO mice compared with vehicle-treated PRLKO animals (20 +/- 0.01 and 60 +/- 10 mg; P < 0.01). We infer that pituitary lactotrophs of PRLKO mice suffer from a dual pathology that includes hypertrophy resulting from endoplasmic reticulum expansion and hyperplasia, with adenomatous transformation, in part as a consequence of disrupted dopaminergic feedback regulation.
Cruz-Soto
Martha E
ME
Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Scheiber
Michael D
MD
Gregerson
Karen A
KA
Boivin
Gregory P
GP
Horseman
Nelson D
ND
D000236:Adenoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001971:Bromocriptine / Q000627:therapeutic use; D004298:Dopamine / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000473:pathology; D004967:Estrogens / Q000097:blood; D005246:Feedback; D005260:Female; D005455:Fluorescent Antibody Technique; D013006:Growth Hormone / Q000032:analysis; D006965:Hyperplasia; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010902:Pituitary Gland / Q000737:chemistry / Q000473:pathology; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011388:Prolactin / Q000032:analysis / Q000172:deficiency* / Q000235:genetics*
D004967:Estrogens; D001971:Bromocriptine; D011388:Prolactin; D013006:Growth Hormone; D004298:Dopamine