ELF3 is a repressor of androgen receptor action in prostate cancer cells.

The androgen receptor (AR) has a critical role in the development and progression of prostate cancer (PC) and is a major therapeutic target in this disease. The transcriptional activity of AR is modulated by the coregulators with which it interacts, and consequently deregulation of cofactor expression and/or activity impacts the expression of genes whose products can have a role in PC pathogenesis. Here we report that E74-like factor 3 (ELF3), a member of the ETS family of transcription factors, is a repressor of AR transcriptional activity. Exogenous expression of ELF3 represses AR transcriptional activity when assessed using reporter-based transfection assays or when evaluated on endogenous AR target genes. Conversely, ELF3 knock down increases the AR transcriptional activity. Biochemical dissection of this activity indicates that it results from the physical interaction between ELF3 and AR and that this interaction inhibits the recruitment of AR to specific androgen response elements within target gene promoters. Significantly, we observed that depletion of ELF3 expression in LNCaP cells promotes cell migration, whereas increased ELF3 expression severely inhibits tumor growth in vitro and in a mouse xenograft model. Taken together, these results suggest that modulation of ELF3 expression and/or AR/ELF3 interaction may have utility in the treatment of PC.

C/EBPalpha redirects androgen receptor signaling through a unique bimodal interaction.

Nuclear expression of CCAAT enhancer binding protein-alpha (C/EBPalpha), which supports tissue differentiation through several antiproliferative protein-protein interactions, augurs terminal differentiation of prostate epithelial cells. C/EBPalpha is also a tumor suppressor, but in many tumors its antiproliferative interactions may be attenuated by de-phosphorylation. C/EBPalpha acts as a corepressor of the classical androgen response element (ARE)-mediated gene activation by the androgen receptor (AR), but this is paradoxical as the genotropic actions of AR are crucial not only for the growth of the prostate but also for its maintenance and function. We show that DNA-bound C/EPBalpha recruits AR to activate transcription. C/EBPalpha-dependent trans-activation by AR also overrode suppression of AREs by C/EBPalpha elsewhere in a promoter. This mechanism was remarkable in that its androgen dependence was apparently for nuclear translocation of AR; it was otherwise androgen independent, flutamide insensitive and tolerant to disruption of AR dimerization. Gene response profiles and global chromatin associations in situ supported the direct bimodal regulation of AR transcriptional signaling by C/EBPalpha. This unique mechanism explains the functional coordination between AR and C/EPBalpha in the prostate and also shows that hormone-refractory AR signaling in prostate cancer could occur through receptor tethering.

Estrogen-induced and TAFII30-mediated gene repression by direct recruitment of the estrogen receptor and co-repressors to the core promoter and its reversal by tamoxifen.

Estradiol (E2) acts through the estrogen receptor (ER) to downregulate many genes, and tamoxifen (Tam) largely reverses this repression but the underlying mechanisms are unclear. Repression of the folate receptor (FR)-alpha P4 core promoter by ER is enhanced by E2 and reversed by Tam. This effect was unaffected by inhibition of new protein synthesis and required the E/F and the DNA-binding domains of ER without direct binding of ER to DNA. The repression by E2/ER was not specific for either Sp1 or TATA elements but was loosely selective for the initiator and flanking sequence. Insertion of a response element or a relatively strong Sp1 cluster to recruit ER upstream of the core promoters caused a switch to activation by E2/ER that was inhibited by Tam. In nuclear extracts, association of ER with a biotinylated core promoter fragment was promoted by E2 but Tam blocked this effect. Repression/de-repression of the P4 promoter and endogenous FR-alpha expression by E2/Tam required SMRT and/or NCoR. ER associated with the chromosomal P4 promoter and SMRT and NCoR associated with it in an ER-dependent manner; these associations were favored by E2 but disrupted by Tam, in the short term, without changes in ER expression. TAFII30 was required for optimal P4 promoter activity and for the repressive association of ER. E2 may thus maintain a low transcriptional status of genes by favoring direct TAFII30-dependent association of ER with the core promoter in a co-repressor complex containing SMRT and/or NCoR; this repression is overridden in target genes containing an upstream element that strongly recruits ER. In addition to suppressing the activation of classical E2 target genes, Tam may upregulate genes by passively dissociating the ER co-repressor complex.

Preterm singleton breech in North Jordan: vaginal versus abdominal delivery.

The safety of vaginal birth for singleton preterm breech has not often been addressed before. We retrospectively compared the perinatal outcome of two groups of preterm breech delivery. Sixty-six patients delivered vaginally and 32 delivered abdominally between 26 and 36 completed weeks. Vaginal delivery was allowed under the same protocol for singleton breech delivery at term. Both groups had similar maternal characteristics. Intergroup differences in early neonatal outcome, as measured by Apgar score, were not significant. Intrapartum and early neonatal deaths in vaginal and cesarean delivery were compared. There was no significant difference in intrapartum death and early neonatal mortality between those who delivered vaginally and those who delivered by cesarean section (16.6 vs. 15.6%). So even with optimum neonatal care facilities, cesarean section does not offer any advantage over vaginal delivery in a developing country. This study does not advocate the routine use of cesarean section for delivering preterm breech fetuses.