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Steroid receptor coactivator-3 (SRC-3), also known as amplified in breast cancer 1 (AIB1), is a member of the SRC family. SRC-3 regulates not only the transcriptional activity of nuclear receptors but also many other transcription factors. Besides the essential role of SRC-3 in physiological functions, it also acts as an oncogene to promote multiple aspects of cancer. This review updates the important progress of SRC-3 in carcinogenesis and summarizes its mode of action, which provides clues for cancer therapy.

Following estrogenic activation, the estrogen receptor-α (ERα) directly regulates the transcription of target genes via DNA binding. MicroRNAs (miRNAs) modulated by ERα have the potential to fine tune these regulatory systems and also provide an alternate mechanism that could impact on estrogen-dependent developmental and pathological systems. Through a microarray approach, we identify the subset of microRNAs (miRNAs) modulated by ERα, which include upregulation of miRNAs derived from the processing of the paralogous primary transcripts (pri-) mir-17-92 and mir-106a-363. Characterization of the mir-17-92 locus confirms that the ERα target protein c-MYC binds its promoter in an estrogen-dependent manner. We observe that levels of pri-mir-17-92 increase earlier than the mature miRNAs derived from it, implicating precursor cleavage modulation after transcription. Pri-mir-17-92 is immediately cleaved by DROSHA to pre-miR-18a, indicating that its regulation occurs during the formation of the mature molecule from the precursor. The clinical implications of this novel regulatory system were confirmed by demonstrating that pre-miR-18a was significantly upregulated in ERα-positive compared to ERα-negative breast cancers. Mechanistically, miRNAs derived from these paralogous pri-miRNAs (miR-18a, miR-19b, and miR-20b) target and downregulate ERα, while a subset of pri-miRNA-derived miRNAs inhibit protein translation of the ERα transcriptional p160 coactivator, AIB1. Therefore, different subsets of miRNAs identified act as part of a negative autoregulatory feedback loop. We propose that ERα, c-MYC, and miRNA transcriptional programs invoke a sophisticated network of interactions able to provide the wide range of coordinated cellular responses to estrogen.

Acute myocardial infarction (AMI) is one of the major causes of death throughout the world, while inflammation has been known as a major contributor to the pathophysiology of AMI. Inhibition of inflammation is shown to protect from AMI. Amplified in breast 1 (Aib1) is a transcriptional coactivator protein which can suppress inflammation. The anti-inflammatory activities of Aib1 imply its potential effects against AMI; however, to date the role of Aib1 in AMI has not been described yet. Here we explored the potential functions of Aib1 in AMI. We induced AMI in both wild-type (WT) and Aib1−/− mice. The expression levels of Aib1 and inflammatory cytokines in the AMI WT mice were measured by RT-PCR and Western blot. The heart infarction area and cardiac functions were compared between the AMI WT and Aib1−/− mice. The expression levels of inflammatory cytokines including IL-6, IL-1β, TNF-α, and MCP-1 in heart tissues were compared between the AMI WT and Aib1−/− mice by ELISA and RT-PCR. AMI induced the production of inflammatory cytokines whereas suppressed the expression of Aib1 in WT mice. AMI Aib1−/− mice displayed increased infarct area and aggravated heart dysfunction, as well as upregulated levels of Il-6, Il-1β, Tnf-α, and Mcp-1 in heart tissues. Aib1 deficiency exacerbates inflammation in AMI mice.Key messagesAMI induced inflammation in the heart tissue of mice.Aib1 knockout exacerbated infarction in AMI mice.Aib1 knockout exacerbated cardiac dysfunction in AMI mice.Aib1 knockout exacerbated inflammation in AMI mice.

Steroid receptor co-activator-3 (SRC-3/AIB1) is an oncogene that is amplified and overexpressed in many human cancers. However, the molecular mechanisms that regulate ‘activated SRC-3 oncoprotein’ turnover during tumorigenesis remain to be elucidated. Here, we report that speckle-type POZ protein (SPOP), a cullin 3 (CUL3)-based ubiquitin ligase, is responsible for SRC-3 ubiquitination and proteolysis. SPOP interacts directly with an SRC-3 phospho-degron in a phosphorylation-dependent manner. Casein kinase Iɛ phosphorylates the S102 in this degron and promotes SPOP-dependent turnover of SRC-3. Short hairpin RNA knockdown and overexpression experiments substantiated that the SPOP/CUL3/Rbx1 ubiquitin ligase complex promotes SRC-3 turnover. A systematic analysis of the SPOP genomic locus revealed that a high percentage of genomic loss or loss of heterozygosity occurs at this locus in breast cancers. Furthermore, we demonstrate that restoration of SPOP expression inhibited SRC-3-mediated oncogenic signaling and tumorigenesis, thus positioning SPOP as a tumor suppressor.

Nuclear retinoic acid (RA) receptors (RARs) activate gene expression through dynamic interactions with coregulators in coordination with the ligand and phosphorylation processes. Here we show that during RA‐dependent activation of the RARα isotype, the p160 coactivator pCIP/ACTR/AIB‐1/RAC‐3/TRAM‐1/SRC‐3 is phosphorylated by p38MAPK. SRC‐3 phosphorylation has been correlated to an initial facilitation of RARα‐target genes activation, via the control of the dynamics of the interactions of the coactivator with RARα. Then, phosphorylation inhibits transcription via promoting the degradation of SRC‐3. In line with this, inhibition of p38MAPK markedly enhances RARα‐mediated transcription and RA‐dependent induction of cell differentiation. SRC‐3 phosphorylation and degradation occur only within the context of RARα complexes, suggesting that the RAR isotype defines a phosphorylation code through dictating the accessibility of the coactivator to p38MAPK. We propose a model in which RARα transcriptional activity is regulated by SRC‐3 through coordinated events that are fine‐tuned by RA and p38MAPK.

Purpose According to the 2017 St Gallen surrogate definitions of the intrinsic subtypes, Ki67, progesterone receptor (PR) and Nottingham histological grade (NHG) are used for prognostic classification of estrogen receptor (ER) positive/HER2-negative breast cancer into luminal A- or luminal B-like. The aim of the present study was to investigate if additional biomarkers, related to endocrine signaling pathways, e.g., amplified in breast cancer 1 (AIB1), androgen receptor (AR), and G protein-coupled estrogen receptor (GPER), can provide complementary prognostic information in a subset of ER-positive/HER-negative invasive lobular carcinoma (ILC). Methods Biomarkers from 224 patients were analyzed immunohistochemically on tissue microarray. The primary endpoint was breast cancer mortality (BCM), analyzed with 10- and 25-year follow-up (FU). In addition, the prognostic value of gene expression data for these biomarkers was analyzed in three publicly available ILC datasets. Results AIB1 (high vs. low) was associated to BCM in multivariable analysis (adjusted for age, tumor size, nodal status, NHG, Ki67, luminal-like classification, and adjuvant systemic therapy) with 10-year FU (HR 6.8, 95% CI 2.3–20, P  = 0.001) and 25-year FU (HR 3.0, 95% CI 1.1–7.8, P  = 0.03). The evidence of a prognostic effect of AIB1 could be confirmed by linking gene expression data to outcome in independent publicly available ILC datasets. AR and GPER were neither associated to BCM with 10-year nor with 25-year FU ( P  > 0.33). Furthermore, Ki67 and NHG were prognostic for BCM at both 10-year and 25-year FU, whereas PR was not. Conclusions AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative ILC.

Background Androgens, through their own receptor, play a protective role on breast tumor development and progression and counterbalance estrogen-dependent growth stimuli which are intimately linked to breast carcinogenesis. Methods Cell counting by trypan blu exclusion was used to study androgen effect on estrogen-dependent breast tumor growth. Quantitative Real Time RT–PCR, western blotting, transient transfection, protein immunoprecipitation and chromatin immunoprecipitation assays were carried out to investigate how androgen treatment and/or androgen receptor overexpression influences the functional interaction between the steroid receptor coactivator AIB1 and the estrogen- or androgen receptor which, in turn affects the estrogen-induced cyclin D1 gene expression in MCF-7 breast cancer cells. Data were analyzed by ANOVA. Results Here we demonstrated, in estrogen receptor α (ERα)-positive breast cancer cells, an androgen-dependent mechanism through which ligand-activated androgen receptor (AR) decreases estradiol-induced cyclin D1 protein, mRNA and gene promoter activity. These effects involve the competition between AR and ERα for the interaction with the steroid receptor coactivator AIB1, a limiting factor in the functional coupling of the ERα with the cyclin D1 promoter. Indeed, AIB1 overexpression is able to reverse the down-regulatory effects exerted by AR on ERα-mediated induction of cyclin D1 promoter activity. Co-immunoprecipitation studies indicated that the preferential interaction of AIB1 with ERα or AR depends on the intracellular expression levels of the two steroid receptors. In addition, ChIP analysis evidenced that androgen administration decreased E 2 -induced recruitment of AIB1 on the AP-1 site containing region of the cyclin D1 gene promoter. Conclusions Taken together all these data support the hypothesis that AIB1 sequestration by AR may be an effective mechanism to explain the reduction of estrogen-induced cyclin D1 gene activity. In estrogen-dependent breast cancer cell proliferation, these findings reinforce the possibility that targeting AR signalling may potentiate the effectiveness of anti-estrogen adjuvant therapies.

Purpose Host factors, including genetic factors, are underutilized in breast cancer treatment selection. This study aimed to investigate AIB1 genotypes as pharmacogenetic markers for adjuvant breast cancer treatment. The prognostic impact of three functional polymorphisms associated with altered mRNA expression rs6094752 (low expression), rs2230782 (low expression) and rs2076546 (high expression) was studied in different treatment groups. Methods AIB1 genotyping was performed using iPLEX™ on 576 breast cancer patients included 2002 − 2008 in Lund, Sweden, who were followed for up to 15 years. Clinicopathological data was obtained from questionnaires and patient charts. Diplotypes were constructed. Survival analyses were conducted with Kaplan-Meier curves, Log-Rank tests and multivariable Cox regression. Results The most common AIB1 diplotypes were CGA_CGA (61.4%), CGA_CCA (16.4%), and CGA_CGG (12.0%). The remaining diplotypes were classified as ‘Rare’. Any breast cancer event was reported in 144 patients. There were significant interactions between radiotherapy and CGA_CGA ( P interaction =0.033) or CGA_CCA ( P interaction =0.017) on prognosis. In the 226 non-radiotherapy-treated patients, CGA_CGA carriers had the best prognosis, and CGA_CCA carriers the worst prognosis, with two-fold risk of breast cancer events in CGA_CCA compared with CGA_CGA carriers. In the 350 radiotherapy-treated patients, CGA_CGA was not associated with prognosis while CGA_CCA conferred 40% lower event risk. No other significant interactions between AIB1 diplotypes and chemotherapy, tamoxifen or aromatase inhibitors on prognosis were observed. Conclusion AIB1 genotypes conferred differential prognostic impact depending on adjuvant radiotherapy. If confirmed, AIB1 merits further evaluation as a putative pharmacogenetic marker to identify patients that benefit the most from radiotherapy.

Background General control non-depressible 5 (GCN5) is a crucial catalytic component of a transcriptional regulatory complex that plays important roles in cellular functions from cell cycle regulation to DNA damage repair. Although GCN5 has recently been implicated in certain oncogenic roles, its role in liver cancer progression remains vague. Results In this study, we report that GCN5 was overexpressed in 17 (54.8 %) of 31 human hepatocellular carcinoma (HCC) specimens. Down-regulation of GCN5 inhibited HCC cell proliferation and xenograft tumor formation. GCN5 knockdown decreased the protein levels of the proliferation marker proliferating cell nuclear antigen (PCNA) and amplified in breast cancer 1 (AIB1), but increased the protein levels of cell cycle inhibitor p21 Cip1/Waf1 in HepG2 cells. GCN5 regulated AIB1 expression, at least in part, by cooperating with E2F1 to enhance AIB1 transcription. Consistently, GCN5 expression was positively correlated with AIB1 expression in human HCC specimens in two GEO profile datasets. Conclusion Since AIB1 plays a promoting role in HCC progression, our results propose that GCN5 promotes HCC progression at least partially by regulating AIB1 expression. This study implicates that GCN5 might be a potential molecular target for HCC diagnosis and treatment.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and devastating cancers without effective treatments. Amplified in breast cancer 1 (AIB1) is a member of the steroid receptor coactivator family that mediates the transcriptional activities of nuclear receptors. While AIB1 is associated with the initiation and progression of multiple cancers, the mechanism by which AIB1 contributes to PDAC progression remains unknown. In this study, we aimed to explore the role of AIB1 in the progression of PDAC and elucidate the underlying mechanisms. The clinical significance and mRNA level of AIB1 in PDAC were studied by database analysis. To demonstrate whether AIB1 mediates the malignant features of PDAC cells, namely, proliferation, migration, invasion, we performed real-time PCR and Western blot analysis, established xenograft models and used metastasis assay. With insights into the mechanism of AIB1, we performed RNA sequencing (Seq), ChIP-Seq, luciferase reporter assays and pull-down assays. Furthermore, we analyzed the relationship between AIB1 expression and its target expression in PDAC cells and patients and explored whether PDAC cells with high AIB1 levels are sensitive to inhibitors of its target. We found that AIB1 was significantly upregulated in PDAC and associated with its malignancy. Silencing AIB1 impaired hedgehog (Hh) activation by reducing the expression of smoothened (SMO), leading to cell cycle arrest and the inhibition of PDAC cell proliferation. In addition, AIB1, upregulation of integrin αv (ITGAV) expression, promoted extracellular matrix (ECM) signaling, which played an important role in PDAC progression. Further studies showed that AIB1 preferably bound to AP-1 related elements and served as a coactivator for enhancing the transcriptional activity of MafB, which promoted the expression of SMO and ITGAV. PDAC cells with high AIB1 levels were sensitive to Hh signaling inhibitors, suggesting that blocking Hh activation is an effective treatment against PDAC with high AIB1 expression. These findings reveal that AIB1 is a crucial oncogenic regulator associated with PDAC progression Hh and ECM signaling and suggest potential therapeutic targets for PDAC treatment.