Pituitary tumor transforming gene overexpression facilitates pituitary tumor development.
Intrinsic and extrinsic stimuli result in profound pituitary growth changes ranging from hypoplasia to hyperplasia. Pituitary tumor transforming gene (PTTG) abundance correlates with pituitary trophic status. Mice with Pttg inactivation exhibit pituitary hypoplasia, whereas targeted pituitary PTTG overexpression driven by alpha-subunit glycoprotein (alphaGSU) promoter results in focal pituitary hyperplasia. To test the impact of pituitary hyperplasia on tumor development, we crossbred alphaGSU.PTTG with Rb+/- mice, which develop pituitary tumors with high penetrance. Pituitary glands of resulting bitransgenic alphaGSU.PTTGxRb+/- mice were compared with monotransgenic alphaGSU.PTTG, Rb+/-, and wild-type mice. Confocal microscopy showed that PTTG-overexpressing cells have enlarged nuclei and marked redistribution of chromatin, and electron microscopy of alphaGSU.PTTG pituitaries showed enlarged gonadotrophs with prominent Golgi complexes and numerous secretory granules. These morphological findings were even more remarkable in alphaGSU.PTTGxRb+/- pituitaries. Mice from all four genotypes were sequentially imaged by magnetic resonance imaging to evaluate pituitary volume, and glands from alphaGSU.PTTGxRb+/- mice were the largest as early as 2 months of age (P = 0.0003). Cumulative incidence of pituitary tumors visualized by magnetic resonance imaging did not differ between Rb+/- and alphaGSU.PTTGxRb+/- mice. However, anterior lobe tumors determined after necropsy were 3.5 times more frequent in alphaGSU.PTTGxRb+/- than in Rb+/- mice (P = 0.0036), whereas the frequency of intermediate lobe tumors was similar. In summary, alphaGSU.PTTGxRb+/- pituitary glands exhibit enhanced cellular activity, increased volume, and higher prevalence of anterior pituitary tumors, indicating that changes in pituitary PTTG content directly relate to both pituitary trophic status and tumorigenic potential.
Donangelo
Ines
I
Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, USA.
Gutman
Shiri
S
Horvath
Eva
E
Kovacs
Kalman
K
Wawrowsky
Kolja
K
Mount
Michael
M
Melmed
Shlomo
S
D000818:Animals; D002843:Chromatin / Q000235:genetics / Q000648:ultrastructure; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006056:Golgi Apparatus / Q000378:metabolism; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009363:Neoplasm Proteins / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000235:genetics*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D022142:Secretory Vesicles / Q000378:metabolism; D064249:Securin
D002843:Chromatin; D009363:Neoplasm Proteins; D018809:Proliferating Cell Nuclear Antigen; D064249:Securin