AIB1 is a novel target of the high-risk HPV E6 protein and a biomarker of cervical cancer progression.

The high-risk human papillomaviruses (HPV-16, -18) are critical etiologic agents in human malignancy, most importantly in cervical cancer. These oncogenic viruses encode the E6 and E7 proteins that are uniformly retained and expressed in cervical cancers and required for maintenance of the tumorigenic phenotype. The E6 and E7 proteins were first identified as targeting the p53 and pRB tumor suppressor pathways, respectively, in host cells, thereby leading to disruption of cell cycle controls. In addition to p53 degradation, a number of other functions and critical targets for E6 have been described, including telomerase, Myc, PDZ-containing proteins, Akt, Wnt, mTORC1, as well as others. In this study, we identified Amplified in Breast Cancer 1 (AIB1) as a new E6 target. We first found that E6 and hTERT altered similar profiling of gene expression in human foreskin keratinocytes (HFK), independent of telomerase activity. Importantly, AIB1 was a common transcriptional target of both E6 and hTERT. We then verified that high-risk E6 but not low-risk E6 expression led to increases in AIB1 transcript levels by real-time RT-PCR, suggesting that AIB1 upregulation may play an important role in cancer development. Western blots demonstrated that AIB1 expression increased in HPV-16 E6 and E7 expressing (E6E7) immortalized foreskin and cervical keratinocytes, and in three of four common cervical cancer cell lines as well. Then, we evaluated the expression of AIB1 in human cervical lesions and invasive carcinoma using immunohistochemical staining. Strikingly, AIB1 showed positivity in the nucleus of cells in the immediate suprabasal epithelium, while nuclei of the basal epithelium were negative, as evident in the Cervical Intraepithelial Neoplasia 1 (CIN1) samples. As the pathological grading of cervical lesions increased from CIN1, CIN2, CIN3 carcinoma in situ and invasive carcinoma, AIB1 staining increased progressively, suggesting that AIB1 may serve as a novel histological biomarker for cervical cancer development. For cases of invasive cervical carcinoma, AIB1 staining was specific to cancerous lesions. Increased expression of AIB1 was also observed in transgenic mouse cervical neoplasia and cancer models induced by E6E7 and estrogen. Knockdown of AIB1 expression in E6E7 immortalized human cervical cells significantly abolished cell proliferation. Taken together, these data support AIB1 as a novel target of HPV E6 and a biomarker of cervical cancer progression.

Loss of ANCO1 repression at AIB1/YAP targets drives breast cancer progression.

Transcription factors critical for the transition of normal breast epithelium to ductal carcinoma in situ (DCIS) and invasive breast cancer are not clearly defined. Here, we report that the expression of a subset of YAP-activated and YAP-repressed genes in normal mammary and early-stage breast cancer cells is dependent on the nuclear co-activator AIB1. Gene expression, sequential ChIP, and ChIP-seq analyses show that AIB1 and YAP converge upon TEAD for transcriptional activation and repression. We find that AIB1-YAP repression of genes at the 1q21.3 locus is mediated by AIB1-dependent recruitment of ANCO1, a tumor suppressor whose expression is progressively lost during breast cancer progression. Reducing ANCO1 reverts AIB1-YAP-dependent repression, increases cell size, and enhances YAP-driven aberrant 3D growth. Loss of endogenous ANCO1 occurs during DCIS xenograft progression, a pattern associated with poor prognosis in human breast cancer. We conclude that increased expression of AIB1-YAP co-activated targets coupled with a loss of normal ANCO1 repression is critical to patterns of gene expression that mediate malignant progression of early-stage breast cancer.

PAX2 promoter methylation and AIB1 overexpression promote tamoxifen resistance in breast carcinoma patients.

INTRODUCTION: Disease recurrence is an important obstacle in estrogen receptor positive (ER+) tamoxifen treated breast carcinoma patients. Tamoxifen resistance-related molecular mechanisms are not fully understood. Alteration in DNA methylation which contributes to transcriptional regulation of cancer-related genes plays a crucial role in tamoxifen response. In the present study, the contribution of promoter methylation and mRNA expression of PAX2 and AIB1 in the development of breast carcinoma and tamoxifen refractory was assessed. METHODS: Methylation specific-high resolution melting (MS-HRM) analysis and Real-time quantitative PCR (RT-qPCR) experiment were performed to analyze the promoter methylation and mRNA expression levels of PAX2 and AIB1 genes in 102 breast tumors and adjacent normal breast specimens. RESULTS: We indicated that PAX2 expression is decreased in breast tissues due to hypermethylation in its promoter region. Compared to the adjacent normal tissues, the tumors exhibited significantly lower relative mRNA levels of PAX2 and increased expression of AIB1. Aberrant promoter methylation of PAX2 and overexpression of AIB1 was observed in tamoxifen resistance patients compared to the sensitive ones. Cox regression analysis exhibited that the increased promoter methylation status of PAX2 and overexpression of AIB1 remained as unfavorable identifiers which influence patients' survival independently. CONCLUSIONS: Our results revealed that the aberration in PAX2 promoter methylation and AIB1 overexpression are associated with the tamoxifen response in breast carcinoma patients. Further research is needed to demonstrate the potential of using PAX2 and AIB1 expression and their methylation-mediated regulation as predictive or prognostic biomarkers or as a new target therapy for better disease management.

Retracted: AIB1 induces epithelial-mesenchymal transition in gastric cancer via the PI3K/AKT signaling.

Amplified in breast cancer 1 (AIB1) is overexpression in various cancers and promotes tumor cell proliferation, survival, and invasiveness. However, the role of AIB1 in the regulation of gastric cancer (GC) cell epithelial-mesenchymal transition (EMT) is still largely unclear. In the present study, immunohistochemistry showed that AIB1 was upregulated in our cohort of patients with GC and correlated with poor survival. Knockdown of AIB1 reduced the invasive ability of GC cells, downregulated the expression of epithelial cell marker E-cadherin, and upregulated mesenchymal cell marker vimentin. AIB1 overexpression elicited the opposite effect. PI-103, the inhibitor of the PI3K/AKT signaling, partially reversed AIB1 overexpression mediated a decrease in E-cadherin and an increase in vimentin. The present data demonstrated that AIB1 augmented the EMT via activation of PI3K/AKT signaling. In conclusion, our results suggested a novel role of AIB1 in GC invasion and EMT and raised the possibility of using this molecule as an indicator for GC treatment.

SRC-3, a Steroid Receptor Coactivator: Implication in Cancer.

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.

The estrogen receptor coactivator AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative invasive lobular carcinoma of the breast.

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.

AIB1 sequestration by androgen receptor inhibits estrogen-dependent cyclin D1 expression in breast cancer cells.

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 E2-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.

Rapid Detection of AIB1 in Breast Cancer Cells Based on Aptamer-Functionalized Nanomotors.

Herein, we report ultrasound-propelled graphene-oxide coated gold nanowire motors, functionalized with fluorescein-labeled DNA aptamers (FAM-AIB1-apt), for qualitative detection of overexpressed AIB1 oncoproteins in MCF-7 breast cancer cells. The movement of nanomotors under the ultrasound field facilitated intracellular uptake and resulted in a faster aptamer binding with the target protein and thus faster fluorescence recovery. The propulsion behavior of the aptamer functionalized nanomotors greatly enhanced the fluorescence intensity compared to static conditions. The new aptamer@nanomotor-based strategy offers considerable potential for further development of sensing methodologies towards diagnosis of breast cancer.

The PI3K and AIB1 interaction is involved in estrogen treated breast cancer cells.

AIB1 was involved in the development and progression of breast cancer. Although it was found that AIB1 could be phosphorylated by some kinases including PI3K, the function of AIB1 and AKT interaction in breast cancer is not well defined. MCF-7 cells were transfected with pERE-Luc AKT and/or AIB1 plasmids, and then ERE luciferase activity in presence or absence of estrogen (E2) were measured. Plasmids containing PTEN and an PI3K inhibitor LY294002 were transfected into or treated cells to identify the interaction of PI3K/AKT and activation of AIB1, and examine their roles in cell cycle regulation. The AKT phosphorylation activity was evaluated by kinase assay using H2B as a substrate. The association between A1B1 and pS2 promoter was detected by the Chromatin Immunoprecipitation (ChIP) assay. AIB1 and AKT in the same complex were detected by Pull-down assay. IGF-1 can increase AIB1 recruitment to PS2 and enhance the ER-dependent transcription activity through the PI3K/AKT pathway. AIB1 associate with AKT to regulate cell cycle. The special relations concerning the AIB1 and AKT may arouse some new viewpoints for potential therapeutic targets in breast cancer.

Prognostic and predictive importance of the estrogen receptor coactivator AIB1 in a randomized trial comparing adjuvant letrozole and tamoxifen therapy in postmenopausal breast cancer: the Danish cohort of BIG 1-98.

PURPOSE: To evaluate the estrogen receptor coactivator amplified in breast cancer 1 (AIB1) as a prognostic marker, as well as a predictive marker for response to adjuvant tamoxifen and/or aromatase inhibitors, in early estrogen receptor-positive breast cancer. METHOD: AIB1 was analyzed with immunohistochemistry in tissue microarrays of the Danish subcohort (N = 1396) of the International Breast Cancer Study Group's trial BIG 1-98 (randomization between adjuvant tamoxifen versus letrozole versus the sequence of the two drugs). RESULTS: Forty-six percent of the tumors had a high AIB1 expression. In line with previous studies, AIB1 correlated to a more aggressive tumor-phenotype (HER2 amplification and a high malignancy grade). High AIB1 also correlated to higher estrogen receptor expression (80-100 vs. 1-79%), and ductal histological type. High AIB1 expression was associated with a poor disease-free survival (univariable: hazard ratio 1.35, 95% confidence interval 1.12-1.63. Multivariable: hazard ratio 1.29, 95% confidence interval 1.06-1.58) and overall survival (univariable: hazard ratio 1.34, 95% confidence interval 1.07-1.68. Multivariable: hazard ratio 1.25, 95% confidence interval 0.99-1.60). HER2 did not seem to modify the prognostic effect of AIB1. No difference in treatment effect between tamoxifen and letrozole in relation to AIB1 was found. CONCLUSIONS: In a subset of the large international randomized trial BIG 1-98, we confirm AIB1 to be a strong prognostic factor in early breast cancer. Hence, although tumor AIB1 expression does not seem to be useful for the choice of tamoxifen versus an aromatase inhibitor in postmenopausal endocrine-responsive breast cancer, AIB1 is an interesting target for new anti-cancer therapies and further investigations of this biomarker is warranted.

Progestin and antiprogestin responsiveness in breast cancer is driven by the PRA/PRB ratio via AIB1 or SMRT recruitment to the CCND1 and MYC promoters.

There is emerging interest in understanding the role of progesterone receptors (PRs) in breast cancer. The aim of this study was to investigate the proliferative effect of progestins and antiprogestins depending on the relative expression of the A (PRA) and B (PRB) isoforms of PR. In mifepristone (MFP)-resistant murine carcinomas antiprogestin responsiveness was restored by re-expressing PRA using demethylating agents and histone deacetylase inhibitors. Consistently, in two human breast cancer xenograft models, one manipulated to overexpress PRA or PRB (IBH-6 cells), and the other expressing only PRA (T47D-YA) or PRB (T47D-YB), MFP selectively inhibited the growth of PRA-overexpressing tumors and stimulated IBH-6-PRB xenograft growth. Furthermore, in cells with high or equimolar PRA/PRB ratios, which are stimulated to proliferate in vitro by progestins, and are inhibited by MFP, MPA increased the interaction between PR and the coactivator AIB1, and MFP favored the interaction between PR and the corepressor SMRT. In a PRB-dominant context in which MFP stimulates and MPA inhibits cell proliferation, the opposite interactions were observed. Chromatin immunoprecipitation assays in T47D cells in the presence of MPA or MFP confirmed the interactions between PR and the coregulators at the CCND1 and MYC promoters. SMRT downregulation by siRNA abolished the inhibitory effect of MFP on MYC expression and cell proliferation. Our results indicate that antiprogestins are therapeutic tools that selectively inhibit PRA-overexpressing tumors by increasing the SMRT/AIB1 balance at the CCND1 and MYC promoters.

Selection and Application of DNA Aptamer Against Oncogene Amplified in Breast Cancer 1.

Amplified in breast cancer 1 (AIB1), also known as steroid receptor coactivator 3 (SRC-3), is a transcriptional coactivator that interacts with nuclear receptors and other transcription factors to enhance their effects on target gene transcription. AIB1, which acts as a major oncogene, is highly expressed in many human cancers, and has been demonstrated to be a key regulator for tumor initiation, progression, metastasis, invasion, and survival. Recruitment of the transcriptional factor CBP/p300 by CBP/p300-interaction domain (CID) of AIB1 is essential for its transcriptional activation function. In this research, we isolated a DNA aptamer AY-3 that binds to AIB1-CID from a random oligonucleotide library using in vitro screening technology-Systematic Evolution of Ligands by EXponential enrichment (SELEX). The binding affinity of the aptamer to AIB1-CID fusion protein is in the nanomolar range. More importantly, the aptamer was found to disrupt in the interaction between p300 and AIB1. This aptamer has great potential to serve as a therapeutic agent for cancer by inhibiting the coactivation of AIB1.

Oestrogen receptor co-activator AIB1 is a marker of tamoxifen benefit in postmenopausal breast cancer.

BACKGROUND: The oestrogen receptor (ER) co-activator amplified in breast cancer 1 (AIB1) has been suggested as a treatment predictive and prognostic marker in breast cancer. Studies have however not been unanimous. PATIENTS AND METHODS: AIB1 protein expression was analysed by immunohistochemistry on tissue micro-arrays with tumour samples from 910 postmenopausal women randomised to tamoxifen treatment or no adjuvant treatment. Associations between AIB1 expression, clinical outcome in the two arms and other clinicopathological variables were examined. RESULTS: In patients with ER-positive breast cancer expressing low tumour levels of AIB1 (<75%), we found no significant difference in recurrence-free survival (RFS) or breast cancer-specific survival (BCS) between tamoxifen treated and untreated patients. In patients with high AIB1 expression (>75%), there was a significant decrease in recurrence rate (HR 0.40, 95% CI 0.26-0.61, P < 0.001) and breast cancer mortality rate (HR 0.38, 95% CI 0.21-0.69, P = 0.0015) with tamoxifen treatment. In the untreated arm, we found high expression of AIB1 to be significantly associated with lower RFS (HR 1.74, 95% CI 1.20-2.53, P = 0.0038). CONCLUSION: Our results suggest that high AIB1 is a predictive marker of good response to tamoxifen treatment in postmenopausal women and a prognostic marker of decreased RFS in systemically untreated patients.

AIB1/SRC-3/NCOA3 function in estrogen receptor alpha positive breast cancer.

The estrogen receptor alpha (ERα) is a steroid receptor that is pivotal in the initiation and progression of most breast cancers. ERα regulates gene transcription through recruitment of essential coregulators, including the steroid receptor coactivator AIB1 (Amplified in Breast Cancer 1). AIB1 itself is an oncogene that is overexpressed in a subset of breast cancers and is known to play a role in tumor progression and resistance to endocrine therapy through multiple mechanisms. Here we review the normal and pathological functions of AIB1 in regard to its ERα-dependent and ERα-independent actions, as well as its genomic conservation and protein evolution. We also outline the efforts to target AIB1 in the treatment of breast cancer.

Aib1 deficiency exacerbates inflammatory responses in acute myocardial infarction mice.

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-1ß, 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-1ß, Tnf-α, and Mcp-1 in heart tissues. Aib1 deficiency exacerbates inflammation in AMI mice. KEY MESSAGES: AMI 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.

Upregulation of amplified in breast cancer 1 contributes to pancreatic ductal adenocarcinoma progression and vulnerability to blockage of hedgehog activation.

Background: 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. Methods: 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 in vivo 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. Results: 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, via 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. Conclusions: These findings reveal that AIB1 is a crucial oncogenic regulator associated with PDAC progression via Hh and ECM signaling and suggest potential therapeutic targets for PDAC treatment.

Employing machine learning and microscopy images of AIB1-stained biopsy material to assess the 5-year survival of patients with colorectal cancer.

Our purpose was to employ microscopy images of amplified in breast cancer 1 (AIB1)-stained biopsy material of patients with colorectal cancer (CRC) to: (a) find statistically significant differences (SSDs) in the texture and color of the epithelial gland tissue, between 5-year survivors and non-survivors after the first diagnosis and (b) employ machine learning (ML) methods for predicting the CRC-patient 5-year survival. We collected biopsy material from 54 patients with diagnosed CRC from the archives of the University Hospital of Patras, Greece. Twenty-six of the patients had survived 5 years after the first diagnosis. We selected regions of interest containing the epithelial gland at different microscope lens magnifications. We computed 69 textural and color features. Furthermore, we identified features with SSDs between the two groups of patients and we designed a supervised ML system for predicting the CRC-patient 5-year survival. Additionally, we employed the VGG16 pretrained convolution neural network to extract deep learning (DL) features, the support vector machines classifier, and the bootstrap cross-validation method for boosting the accuracy of predicting 5-year survival. Fourteen features sustained SSDs between the two groups of patients. The supervised ML system achieved 87% accuracy in predicting 5-year survival. In comparison, the DL system, using images from all magnifications, gave 97% classification accuracy. Glandular texture in 5-year non-survivors appeared to be of lower contrast, coarseness, roughness, local pixel correlation, and lower AIB1 variation, all indicating loss of textural definition. The supervised ML system revealed useful information regarding features that discriminate between 5-year survivors and non-survivors while the DL system displayed superior accuracy by employing DL features.

SRC-3/AIB-1 may Enhance Hepatic NFATC1 Transcription and Mediate Inflammation in a Tissue-Specific Manner in Morbid Obesity.

BACKGROUND: Obesity is a global epidemic which is associated with several cardiometabolic comorbidities and is characterized by chronic, low grade systemic inflammation. Numerous biomarkers have been implicated in the pathophysiology of the disease, including transcription factors and coregulators. Steroid Receptor Coactivator (SRC)-family represent the master regulators of metabolic pathways and their dysregulation is strongly associated with numerous metabolic disorders. METHODS: 50 morbidly obese patients participated in the present study. Biopsies were collected from visceral adipose tissue, subcutaneous adipose tissue, skeletal muscle, extra-myocellular adipose tissue and liver. We evaluated the differential protein expression of NFATc1, SRC-2/TIF-2, SRC-3/AIB-1 and inflammatory biomarkers CD68 and CD3 by immunohistochemistry. The current study was designed to determine any correlations between the transcription factor NFATc1 and the SRC coregulators, as well as any associations with the inflammatory biomarkers. RESULTS: We identified SRC-3 as a hepatic NFATc1 coactivator and we demonstrated its possible role in energy homeostasis and lipid metabolism. Moreover, we revealed a complex and extensive intraand inter-tissue network among the three main investigated proteins and the inflammatory biomarkers, suggesting their potential participation in the obesity-induced inflammatory cascade. CONCLUSION: Steroid receptor coactivators are critical regulators of human metabolism with pleiotropic and tissue-specific actions. We believe that our study will contribute to the better understanding of the complex multi-tissue interactions that are disrupted in obesity and can therefore lead to numerous cardiometabolic diseases. Further on, our present findings suggest that SRC-3/AIB-1 could constitute possible future drug targets.

Impact of AIB1 expression on the prognosis of upper tract urothelial carcinoma after radical nephroureterectomy.

BACKGROUND: Amplified in breast cancer 1 (AIB1) is a candidate oncogene in human breast cancer, which has been identified to be amplified and overexpressed in several types of other human cancers. Abnormalities of AIB1 and its clinical/prognostic significance, however, in upper tract urothelial carcinoma (UTUC) remain unclear. OBJECTIVE: To explore what role AIB1 plays in upper tract urothelial carcinoma. METHODS: The expression of AIB1 was analyzed using immunohistochemical staining in 133 UTUC patients. Overall, cancer specific and recurrence-free survival rates (OS, CSS, and RFS) were estimated using the Kaplan-Meier method. Multivariable COX regression models containing relevant clinicopathological variables addressed the prediction of postoperative outcome. RESULTS: High AIB1 expression was observed to be associated with increased hazard ratios for 5-year CSS (80.6% vs. 55.8%, p= 0.008) and OS (78.1% vs. 54.8%, p= 0.006). Multivariable analysis revealed that elevated AIB1 expression was an independent prognostic predictor of OS, CSS and RFS. Additionally, pT, pN and hydronephrosis were independently associated with oncologic outcome of UTUC. Three proposed nomograms were proposed to provide an individualized risk estimate of postoperative outcome in patients with UTUC. CONCLUSIONS: AIB1 can be used as an independent molecular marker for the prognosis of clinical outcomes of UTUC.

AIB1 predicts tumor response to definitive chemoradiotherapy and prognosis in cervical squamous cell carcinoma.

Amplified in breast cancer 1 (AIB1) gene, has been reported to be associated with biological malignancy in several cancers. However, the molecular status of the AIB1 gene in cervical cancer and the clinicopathological/prognostic significance of AIB1 expression in chemoradiotherapy (CRT) sensitivity have not been determined. In our present study, we found that the high expression of AIB1 was frequent detected in specimens of cervical cancer patients, and this was significantly correlated with CRT response (P = 0.014), clinical stage (P = 0.003), T status (P = 0.027), N status (P = 0.021), M status (P = 0.015) and progression-free survival (P < 0.001). Moreover, the clonogenic survival fraction and cell apoptosis experiments showed that knockdown of AIB1 substantially increased cervical cancer cells sensitivity to ionizing radiation (IR) or cisplatin/5-fluorouracil. Collectively, our results demonstrated that the high expression of AIB1 in cervical cancer cells contributes to the resistance to CRT, which provides the evidence that AIB1 may be a promising predictor of aggressive cervical cancer patients with poor response to CRT.