Up-regulation of nuclear receptor corepressor (NCoR) in progestin-induced growth suppression of endometrial hyperplasia and carcinoma.
BACKGROUND
Although progestins have been used for the treatment of endometrial neoplasias, the mechanisms of progestin-induced growth suppression remain undetermined.


METHODS
Immunostaining for steroid receptor coactivators (SRC-1, p300/CBP), corepressors (NCoR, SMRT) and Ki-67 in 15 neoplastic endometria before and after the treatment with medroxyprogesterone acetate (MPA) was performed. The effect of progestin on cell proliferation and cofactors expression were examined using T47D cells.


RESULTS
Of the 15 cases, 10 showed good histological responses to MPA (Responder) and 5 poor responses (Non-responder). In Responders, MPA treatment resulted in reduced expression of Ki-67 by 78% (p=0.0076) along with increased NCoR expression by 158 % (p=0.0077). Progestin treatment for T47D cells resulted in up-regulation of NCoR mRNA and protein with the suppression of cell proliferation. Immunoprecipitation revealed that NCoR was bound to estrogen receptor alpha, but not to progesterone receptor in T47D cells.


CONCLUSIONS
The up-regulation of NCoR by progestins is associated with the suppression of estrogen-induced growth of neoplastic cells.
Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
Hiroyasu
H
Kashima
Akiko
A
Horiuchi
Junko
J
Uchikawa
Tsutomu
T
Miyamoto
Akihisa
A
Suzuki
Takashi
T
Ashida
Ikuo
I
Konishi
Tanri
T
Shiozawa
D000328:Adult; D015153:Blotting, Western; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004714:Endometrial Hyperplasia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D056920:Nuclear Receptor Coactivator 1; D011372:Progestins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D055815:Young Adult; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D004268:DNA-Binding Proteins; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D011372:Progestins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D012097:Repressor Proteins; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D050880:p300-CBP Transcription Factors