Disease relevance of NCOA3

• In contrast, NCOA3 deficiency suppresses v-Ha-ras-induced breast cancer initiation and progression in mice [1].
• The NCOA3 mRNA encodes a nuclear receptor co-activator that is amplified and over-expressed in a high proportion of breast and ovarian cancers [2].
• At 13 months of age, mammary ductal ectasia was found in CMV-AIB1/ACTR-Delta3 mice, but secondary and tertiary branching patterns were normal [3].
• To determine the role of AIB1-Delta3 in breast cancer pathogenesis, we generated transgenic mice with human cytomegalovirus immediate early gene 1 (hCMVIE1) promoter-driven over-expression of human AIB1/ACTR-Delta3 (CMVAIB1/ACTR-Delta3 mice) [3].
• AIB1 expression correlates with older age (P=0.003), peri- or postmenopausal status (P=0.002) and a higher grade of carcinomas (P=0.04) [4].

Psychiatry related information on NCOA3

• Like earlier cognitive models such as SOAR, ACT-R, 3CAPS, and EPIC, the proposed cognitive model is implemented in a computer simulation that predicts observable variables such as human response times and error patterns [5].
• ACT-R/PM can model simple dual tasks such as the psychological refractory period (PRP), including subtle results previously explained with executive process interactive control (EPIC, D. E. Meyer & D. E. Kieras, 1997a) [6].
• METHOD: An integrated driver model developed in the ACT-R (Adaptive Control of Thought-Rational) cognitive architecture is described that focuses on the component processes of control, monitoring, and decision making in a multilane highway environment [7].

High impact information on NCOA3

• Cellular levels of REGgamma expression affect estrogen-receptor target-gene expression and cell growth as a result of its ability to promote degradation of the SRC-3 protein [8].
• Steroid receptor coactivator-3 (SRC-3/AIB1) is an oncogene frequently amplified and overexpressed in breast cancers [8].
• In exploring the underlying mechanism, we found that the acetylase ACTR can be acetylated by p300/CBP [9].
• In addition, and unexpectedly, we show that purified ACTR is a potent histone acetyltransferase and appears to define a distinct evolutionary branch to this recently described family [10].
• A critical component of the innate immune system, TLRs utilize leucine-rich-repeat motifs for ligand binding and a shared cytoplasmic domain to recruit the adaptors MyD88, TRIF, TIRAP, and/or TRAM for downstream signaling [11].

Chemical compound and disease context of NCOA3

• NCOA3 is overexpressed in approximately 60% of primary human breast tumors, and high levels of NCOA3 expression are associated with tamoxifen resistance and worse survival rate [1].
• Patients whose tumors showed elevated expression of NCOA3 (AIB1) had significantly shorter disease-free (P = 0.017) and overall (P = 0.0021) survival times after surgery than did other patients with breast tumors [12].
• Here, we report the use of chromatin immunoprecipitation (ChIP)-based assays that involve genomic mapping and computational analyses of immunoprecipitated DNA to identify SRC-3-binding target genes in estradiol (E2)-treated MCF-7 breast cancer cells [13].
• We propose that when AIB1 is overexpressed in endometrial carcinoma, ER action is augmented, leading to endometrial hyperplasia and progression to malignancy [4].
• Furthermore, with decreased SRC-3 expression, proliferating cell nuclear antigen and Bcl-2 expression, as well as bromodeoxyuridine incorporation in prostate cancer cells are reduced [14].

Biological context of NCOA3

• For example, men with the 29/29 genotype had 6% or nearly 0.5 sd lower spine BMD than men without this genotype, and NCOA3 genotype explained 3.2% of the phenotypic variation in this trait [15].
• Men were genotyped for a CAG/CAA repeat polymorphism in NCOA3, which encodes a polyglutamine tract of variable length in the C-terminal transcriptional activation domain of the protein [15].
• OBJECTIVE: The aim of this study was to examine the relationships between the CAG/CAA (glutamine) length variation at the NCOA3 locus, sex steroid hormone, and IGF-I levels and bone mineral density (BMD) in a cohort of older Caucasian men [15].
• Here, we analyzed the influence of NCOA3 coding single nucleotide polymorphisms on breast cancer risk by performing a case-control study using a German and a Polish study population and identified an association between NCOA3 polymorphisms and breast cancer [1].
• Steroid receptor coactivator-3 (SRC-3/AIB1) is a coactivator for nuclear receptors and other transcription factors and an oncogene that contributes to growth regulation and development of mammary and other tumor types [13].

Anatomical context of NCOA3

• AIB1/ACTR-Delta3 transgene mRNA expression was confirmed in CMV-AIB1/ACTR-Delta3 mammary glands by in situ hybridization [3].
• These data indicate that overexpression of the AIB1/ACTR-Delta3 isoform resulted in altered mammary epithelial cell growth [3].
• In endometrial carcinoma, there is a higher expression of AIB1 compared to carcinoma-associated complex atypical hyperplasia (0.007) or carcinoma-associated normal endometrium (<0.001) [4].
• All members of the co-regulatory protein family were detected in both, benign and matching malignant tissue samples, except for AIB1, which was found to be expressed exclusively in malignant epithelium [16].
• AIB1 amplification and overexpression were observed in four of five estrogen receptor-positive breast and ovarian cancer cell lines [17].

Associations of NCOA3 with chemical compounds

• Both E2-dependent and -independent SRC-3/ERalpha-binding sites were identified [13].
• Here, we show that overexpression of ACTR not only enhances estrogen-stimulated cell proliferation but also, more strikingly, completely negates the cell cycle arrest effect by tamoxifen and pure antiestrogens [18].
• Mutations of the ERalpha DNA binding domain did not block this rapid E2-dependent SRC-3 phosphorylation [19].
• In response to serum stimulation, AR and ACTR are recruited to the corresponding target gene promoters to activate their expression in androgen-independent manner [20].
• AIB1 expression correlated with ER (r=0.30, P=0.006) [4].

Physical interactions of NCOA3

• Rapid estrogen-induced phosphorylation of the SRC-3 coactivator occurs in an extranuclear complex containing estrogen receptor [19].
• Consistent with this finding, we demonstrated that methylation promotes dissociation of the SRC-3/CARM1 coactivator complex [21].
• Here we show that the receptor-associated coactivator 3 (RAC3) uses two separate LXXLL motifs to bind RAR and RXR [22].
• These results suggest a mechanism for formation of the complex where the unfolded ACTR domain interacts with the partly folded CBP domain in a rapid and specific manner to form the final stable complex [23].
• Binding to DRIP occurs in the undifferentiated keratinocyte, but, as the cell differentiates, DRIP(205) levels fall and p160/SRC binding takes over as SRC3 expression increases [24].

Enzymatic interactions of NCOA3

• In addition, we showed that SRC-3 was phosphorylated by the IKK complex in vitro [25].

Co-localisations of NCOA3

• In human testis, immunostaining of SRC-3 colocalized with AR in nuclei of Sertoli cells and peritubular myoid cells, indicating it could function as an AR coactivator in these cells [26].

Regulatory relationships of NCOA3

• Elevation of ACTR in quiescent cells strongly stimulates the transcription of a subset of E2F-responsive genes that are associated with the G(1)/S transition [18].
• Using phosphospecific antibodies for six phosphorylation sites, we investigated the mechanisms involved in estradiol (E2)-induced SRC-3 phosphorylation and found that this occurs only when either activated estrogen receptor alpha (ERalpha) or activated ERbeta is present [19].
• Signaling through the HER-2 receptor pathway activates AIB1 by phosphorylation [27].
• SRC3 overexpression failed to enhance estrogen-dependent transcription of any ER combination in OBs [28].
• Furthermore, the receptor tyrosine kinase HER2/Neu, an oncoprotein particularly found overexpressed in breast tumors, cooperates with both ACTR and p300 to stimulate ER81-mediated transcription [29].

Other interactions of NCOA3

• Our results provide evidence for an early nongenomic action of ER on SRC-3 that supports the well-established downstream genomic roles of estrogen and coactivators [19].
• ACTR/AIB1 functions as an E2F1 coactivator to promote breast cancer cell proliferation and antiestrogen resistance [18].
• Taken together, our results not only reveal the IKK-mediated phosphorylation of SRC-3 to be a regulated event that plays an important role but also substantiate the role of SRC-3 in multiple signaling pathways [25].
• Furthermore, this article also reviews our current understanding of the role of SRC-3 in breast cancer and discusses possible mechanisms for functional specificity and redundancy among SRC family members [30].
• Furthermore, protein levels of ER-beta p300/CBP and AIB1 were higher in invasive ductal carcinomas than in normal mammary tissue [16].
• SUG-1 also mediates the proteasomal degradation of SRC-3 [31].

Analytical, diagnostic and therapeutic context of NCOA3

• METHODS: The effects of ACTR and androgen receptor (AR) depletion on cell proliferation and gene expression and their functions were analyzed in a panel of androgen-dependent and -independent CaP cells and CWR22 xenograft [20].
• Accumulated results from both ex vivo and animal model studies indicate that SRC-3 plays important roles in many biological processes involving cell proliferation, cell migration, cell differentiation, somatic growth, sexual maturation, female reproductive function, vasoprotection and breast cancer [32].
• METHODS: AIB1 and HER-2 protein levels in tumors from 316 breast cancer patients were determined using western blot analysis [27].
• We report here a ligand-specific interaction of endogenous human ER (hER) and the AIB1 coactivator in MCF-7 human breast cancer cells by using immunoprecipitation analyses [33].
• Molecular cloning of xSRC-3, a novel transcription coactivator from Xenopus, that is related to AIB1, p/CIP, and TIF2 [34].

References