Development of cystic glandular hyperplasia of the endometrium in Mullerian inhibitory substance type II receptor-pituitary tumor transforming gene transgenic mice.
The pituitary tumor transforming gene (PTTG)/securin is an oncogene that is involved in cell cycle regulation and sister chromatid separation. PTTG is highly expressed in various tumors including ovarian tumors, suggesting that PTTG may play a role in ovarian tumorigenesis. Overexpression of PTTG resulted in induction of cellular transformation in vitro and tumor formation in nude mice. To ascertain PTTG function in ovarian tumorigenesis, we generated a transgenic mouse model of PTTG by cloning PTTG cDNA downstream of Mullerian inhibitory substance type II receptor gene promoter (MISIIR) in order to target the ovarian surface epithelium. By screening of transgenic animals, we identified five founders (four males and one female). Using the four male founders, we developed four transgenic lines. PTTG expression was increased in ovarian surface epithelium, ovarian granulosa cells, as well as in the pituitary gland. Transgenic females did not develop any visible ovarian tumors at 8-10 months of age; however, there was an overall increase in the corpus luteum mass in transgenic ovary, suggesting increased luteinization. These changes were associated with an increase in serum LH and testosterone levels. In addition, there was a generalized hypertrophy of the myometrium of MISIIR-PTTG transgenic uteri with cystic glandular and hyperplasia of the endometrium. Based on these results, we conclude that the overexpression of PTTG may be required to initiate precancerous conditions but is not sufficient to induce ovarian tumorigenesis and may require another partner to initiate cellular transformation.
El-Naggar
Shahenda M
SM
Department of Biochemistry and Molecular Biology, University of Louisville, Kentucky 40202, USA.
Malik
Mohammad T
MT
Martin
Alvin
A
Moore
Joseph P
JP
Proctor
Mary
M
Hamid
Tariq
T
Kakar
Sham S
SS
D000818:Animals; D015139:Blotting, Southern / Q000379:methods; D003338:Corpus Luteum / Q000378:metabolism / Q000473:pathology; D004714:Endometrial Hyperplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D006107:Granulosa Cells / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007986:Luteinizing Hormone / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009215:Myometrium / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010053:Ovary / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics* / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D064249:Securin; D013739:Testosterone / Q000097:blood
D009363:Neoplasm Proteins; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D064249:Securin; C084621:anti-Mullerian hormone receptor; D013739:Testosterone; D007986:Luteinizing Hormone