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. Materials and 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 α, but not to progesterone receptor in T47D cells. Conclusion: The up-regulation of NCoR by progestins is associated with the suppression of estrogen- induced growth of neoplastic cells. A subset of endometrial hyperplasia and carcinoma expresses estrogen receptors (ER) and progesterone receptors (PR), and their proliferation is known to be stimulated by estrogen and suppressed by progesterone (1). Progesterone-derivatives such as medroxyprogesterone acetate (MPA) also suppress the growth of endometrial hyperplasia and carcinoma expressing PR, and have been used for the treatment of patients with these diseases (2). The mechanisms of progestin-induced growth suppression of endometrial glandular cells have been investigated in several aspects such as down-regulation of ERs (3, 4), altered levels of steroid metabolizing enzymes (5), growth factors or cytokines (6), and up-regulation of p27Kip1 (7). These steroid hormone- related growth mechanisms have been generally considered to be mediated via their receptors, however, the molecular pathways downstream of the receptors that promote the transcription of target genes have not been fully elucidated. Recent research has identified a group of molecules termed as steroid receptor cofactors (8). These factors bind to steroid receptors in a ligand-dependent fashion, and the receptor- bound cofactors then bind to the basal transcriptional machineries of the target genes, resulting in transcription. Thus, the steroid receptor cofactors are important molecules intervening between the receptors and target genes. These cofactors are now functionally divided into two subclasses, i.e., coactivators and corepressors. The former stimulates, and the latter suppresses the transcription of target genes. The cyclic changes in the expression of the two coactivators, steroid receptor coactivator-1 (SRC-1) (9) and cyclic AMP- response element-binding protein, a substantial homologue of p300 (p300/CBP) (10) in normal human endometrium (11) have been previously reported. The reduced expression of SRC-1 and p300/CBP in endometrial carcinoma, as well as increased expression of a corepressor, nuclear receptor corepressor (NCoR) (12), in endometrial hyperplasia (13) have also been reported. However, the involvement of these cofactors in endometrial hyperplasia treated with progestins has not been elucidated. In the present study, the expression of two representative coactivators (SRC-1 and p300/CBP), and two corepressors (NCoR and silencing mediator for retinoid and thyroid-hormone receptors, SMRT (14) were immunohistochemically examined in neoplastic endometrial tissues treated with progestin. Furthermore, the functional