Aberrant Ki-67 expression through 3'UTR alternative polyadenylation in breast cancers.
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ABSTRACT:
SUBMITTER: Yan H
PROVIDER: S-EPMC5832968 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Ki-67 serves as a prominent cancer marker. We describe how expression of the MKI67 gene coding for Ki-67 is controlled during the cell cycle. MKI67 mRNA and Ki-67 protein are maximally expressed in G2 phase and mitosis. Expression is dependent on two CHR elements and one CDE site in the MKI67 promoter. DREAM transcriptional repressor complexes bind to both CHR sites and downregulate the expression in G0/G1 cells. Upregulation of MKI67 transcription coincides with binding of B-MYB-MuvB and FOXM1-MuvB complexes from S phase into G2/M. Importantly, binding of B-MYB to the two CHR elements correlates with loss of CHR-dependent MKI67 promoter activation in B-MYB-knockdown experiments. In knockout cell models, we find that DREAM/MuvB-dependent transcriptional control cooperates with the RB Retinoblastoma tumor suppressor. Furthermore, the p53 tumor suppressor indirectly downregulates transcription of the MKI67 gene. This repression by p53 requires p21/CDKN1A. These results are consistent with a model in which DREAM, B-MYB-MuvB, and FOXM1-MuvB together with RB cooperate in cell cycle-dependent transcription and in transcriptional repression following p53 activation. In conclusion, we present mechanisms how MKI67 gene expression followed by Ki-67 protein synthesis is controlled during the cell cycle and upon induction of DNA damage, as well as upon p53 activation.
| S-EPMC8629999 | biostudies-literature
Project description:Most eukaryotic genes express alternative polyadenylation (APA) isoforms with different 3'UTR lengths, production of which is influenced by cellular conditions. Here, we show that arsenic stress elicits global shortening of 3'UTRs through preferential usage of proximal polyadenylation sites during stress and enhanced degradation of long 3'UTR isoforms during recovery. We demonstrate that RNA-binding protein TIA1 preferentially interacts with alternative 3'UTR sequences through U-rich motifs, correlating with stress granule association and mRNA decay of long 3'UTR isoforms. By contrast, genes with shortened 3'UTRs due to stress-induced APA can evade mRNA clearance and maintain transcript abundance post stress. Furthermore, we show that stress causes distinct 3'UTR size changes in proliferating and differentiated cells, highlighting its context-specific impacts on the 3'UTR landscape. Together, our data reveal a global, 3'UTR-based mRNA stability control in stressed cells and indicate that APA can function as an adaptive mechanism to preserve mRNAs in response to stress.
| S-EPMC5995920 | biostudies-literature
Project description:Several studies have shown that estrogen receptor (ER) and progesterone receptor (PR) expression and human epidermal growth factor receptor 2 (HER2) expression may vary during tumoral progression. We aimed to describe and compare ER, PR, and HER2 expressions in primary breast tumors and synchronic axillary nodal metastases, and evaluate phenotypic correlations between them.Patients were identified prospectively through surgical procedures between September 2013 and July 2016. The status of ER, PR, HER2, and Ki-67 were pathologically analyzed in breast cancers and axillary nodal metastases; these patients were classified based on the breast cancer phenotypes into five subgroups.Synchronic axillary nodal metastases were observed in 127 patients. In breast cancers and nodal metastases, correlation analyses of ER, PR, and Ki-67 expression showed a statistical dependence and concordance between these samples was unambiguously demonstrated through Bland-Altman plots for each determination. Primary breast tumors were classified as follows: luminal A, 41.6%; luminal B, 40.0%; luminal B/HER2, 9.6%; HER2, 2.4%; triple negative, 6.4%. Alterations in phenotype were observed in 28% of patients. The most frequent phenotypic alteration was from luminal B to A (36.4%). Ten cases (30.3%) showed alterations with therapeutic implications; six gained HER2 overexpression, and four, hormonal receptor (HR) expression. A moderate strength of agreement (Cohen's κ coefficient, 0.59; 95% confidence interval, 0.48-0.71) was observed. In multivariate analyses, high histologic grade (odds ratio [OR], 2.79; p<0.047) and high Ki-67 expression (OR, 1.05; p<0.037) were independent factors predictive of phenotypic alterations.Strong correlations were observed in HR and Ki-67 expressions between primary breast tumors and axillary nodal metastases, and a moderate concordance was observed in their phenotypical characteristics. Nevertheless, alterations did exist, and one-third of these changes may have therapeutic implications. The nodal metastases of tumors with high grade and high Ki-67 expression may need to be analyzed, to obtain complete therapeutic information.
| S-EPMC5500400 | biostudies-other
Project description:PurposeTriple-negative breast cancer (TNBC) is a subset of breast cancer which is known to carry a poor prognosis because of lack of targets for hormonal therapy. Research efforts have focused in recent years on discovering biomarkers of management in TNBCs. KI-67 Labelling Index (LI) is a nuclear protein which has proven to play diagnostic and prognostic roles in many cancers.Materials and methodsWe analysed the expression of KI-67 LI by immunohistochemistry in TNBC cases from the University hospital. This expression was cross-checked against clinical-pathological criteria of TNBC patients and against Vimentin expression in TNBC patients with significant KI-67 expression.ResultsKI-67 LI was significantly expressed in the majority of TNBC cases. This expression was significantly correlated with lymph node metastases, tumour invasion, high tumour nuclear grade, clinical stage, adverse survival outcome, and failure to achieve pathological complete response. TNBCs' KI-67 LI expression was also correlated with Vimentin expression, the mesenchymal chief marker of the EMT phenomenon.ConclusionCollectively, our study presents a strong argument for the use of KI-67 LI as a biomarker of aggressive, metastatic TNBC disease with poor outcome. This study, along with mounting evidence in the scientific literature, presents a case for the use of this nuclear protein in diagnosis, prognosis, and follow-up of patients with this difficult diagnosis.
| S-EPMC8186110 | biostudies-literature
Project description:Triple-negative breast cancers (TNBCs) often have a high Ki-67 proliferation index and respond favorably to neoadjuvant chemotherapy (NACT) with pathologic complete response (pCR) resulting in ~40% of cases. Nevertheless, morbidity/mortality remain high, mostly due to recurrence in patients with residual disease. In contrast, the incidence and clinical features of TNBC with low proliferation (TNLP), defined as TNBC with a Ki-67 index of ≤30% remains unknown. We report 70 cases of TNLP identified at our center from 2008 to 2018, including 18 treated with NACT. TNLP tumors represent <1% of all breast cancers, and ~5-10% of TNBCs. Ninety percent of carcinomas were grade I/II and 70% were either pure apocrine or showed apocrine differentiation. Fifty cases had available immunohistochemistry results; 80%, 84%, 22%, and 20% were positive for AR, INPP4B, nestin, and SOX10, respectively. With a median follow-up of 72 months, 14% experienced recurrence, and 11% died of breast cancer. The tumor stage was prognostic. Among 39 stage-I patients, 18 (46%) received chemotherapy, but this did not impact survival. There was a trend for improved recurrence-free survival with chemotherapy in stage-II patients. Of the 18 patients treated with NACT, 2 (11%) showed pCR; these were notable for either high stromal TILs or a high mitotic count despite a low Ki-67 index. TNLPs are enriched in low to intermediate-grade carcinomas with apocrine features. Due to overall good prognosis of stage-I TNLP and the lack of clear benefit of chemotherapy, de-escalation of chemotherapy may be considered in select patients with stage-I TNLP.
| S-EPMC9021249 | biostudies-literature
Project description:Background: Triple-negative breast cancer (TNBC) is an aggressive malignancy with high heterogeneity. However, the alternative polyadenylation (APA) profiles of TNBC remain unknown. Here, we aimed to define the characteristics of the APA events at post-transcription level among TNBCs. Methods: Using transcriptome microarray data, we analyzed APA profiles of 165 TNBC samples and 33 paired normal tissues. A pooled short hairpin RNA screen targeting 23 core cleavage and polyadenylation (C/P) genes was used to identify key C/P factors. Results: We established an unconventional APA subtyping system composed of four stable subtypes: 1) luminal androgen receptor (LAR), 2) mesenchymal-like immune-activated (MLIA), 3) basal-like (BL), 4) suppressed (S) subtypes. Patients in the S subtype had the worst disease-free survival comparing to other patients (log-rank p = 0.021). Enriched clinically actionable pathways and putative therapeutic APA events were analyzed among each APA subtype. Furthermore, CPSF1 and PABPN1 were identified as the master C/P factors in regulating APA events and TNBC proliferation. The depletion of CPSF1 or PABPN1 weakened cell proliferation, enhanced apoptosis, resulted in cell cycle redistribution and a reversion of APA events of genes associated with tumorigenesis, proliferation, metastasis and chemosensitivity in breast cancer. Conclusions: Our findings advance the understanding of tumor heterogeneity regulation in APA and yield new insights into therapeutic target identification in TNBC.
| S-EPMC7482814 | biostudies-literature
Project description:BackgroundRho GTPase-activating protein 10 (ARHGAP10), which catalyzes the conversion of active Rho GTPase to the inactive form, is downregulated in some cancers. However, little is known about ARHGAP10 in breast cancer.MethodsThe transcriptional expression level of ARHGAP10 in breast cancer was analyzed with the data downloaded from The Cancer Genome Atlas (TCGA) and Oncomine, then verified by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in 30 pairs of breast cancer tissues and the corresponding adjacent normal tissues. ARHGAP10 protein expression was examined by immunohistochemistry (IHC) in 190 breast cancer and 30 corresponding adjacent normal breast tissue samples. The associations between ARHGAP10 expression and clinicopathological characteristics of patients were analyzed, and Kaplan-Meier Plotter was used to assess the relationship between ARHGAP10 and relapse-free survival (RFS). Different expression levels of ARHGAP10 in response to chemotherapy agents were determined by GEO2R online tool. The potential biological functions of ARHGAP10 were analyzed by Gene Set Enrichment Analysis (GSEA) using data downloaded from TCGA.ResultsARHGAP10 mRNA and protein expression was lower in breast cancer tissues than in adjacent normal tissues. Low expression of ARHGAP10 was associated with advanced clinical TNM (cTNM) stage (p b = 0.001) and high Ki-67 index (p = 0.015). Low expression of ARHGAP10 indicated worse RFS (p = 0.0015) and a poor response to chemotherapy (p = 0.006). GSEA results showed that ARHGAP10 was involved in signaling pathways including protein export, nucleotide excision repair, base excision repair, focal adhesion, JAK-STAT pathway and the actin cytoskeleton.
| S-EPMC6679923 | biostudies-literature
Project description:This study aimed to optimize slope and energy levels for evaluating Ki-67 expression in lung cancer using virtual monoenergetic imaging and compare the predictive efficiency of different energy spectrum slopes (λHU) for Ki-67. Forty-three patients with primary lung cancer confirmed via pathological examination were enrolled in this study. They underwent baseline arterial-phase (AP) and venous-phase (VP) energy spectrum computed tomography (CT) scanning before surgery. The CT values were 40-190 keV, with 40-140 keV indicating pulmonary lesions at AP and VP, and P < 0.05 indicating a statistically significant difference. An immunohistochemical examination was conducted, and receiver operating characteristic curves were used to analyze the prediction performance of λHU for Ki-67 expression. SPSS Statistics 22.0 (IBM Corp., NY, USA) was used for statistical analysis, and χ2, t, and Mann-Whitney U tests were used for quantitative and qualitative analyses of data. Significant differences were observed at the corresponding CT values of 40 keV (as 40-keV is considered the best for single-energy image for evaluating Ki-67 expression) and 50 keV in AP and at 40, 60, and 70 keV in VP between high- and low-Ki-67 expression groups (P < 0.05). In addition, the λHU values of three-segment energy spectrum curve in both AP and VP were quite different between two groups (P < 0.05). However, the VP data had greater predictive values for Ki-67. The areas under the curve were 0.859, 0.856, and 0.859, respectively. The 40-keV single-energy sequence was the best single-energy sequence to evaluate the expression of Ki-67 in lung cancer and to obtain λHU values using the energy spectrum curve in the VP. The CT values had better diagnostic efficiency.
| S-EPMC9992396 | biostudies-literature
Project description:Cigarette smoking induces a profound transcriptomic and systemic inflammatory response. Previous studies have focused on gene level differential expression of smoking, but the genome-wide effects of smoking on alternative isoform regulation have not yet been described. We conducted RNA sequencing in whole-blood samples of 454 current and 767 former smokers in the COPDGene Study, and we analyzed the effects of smoking on differential usage of isoforms and exons. At 10% FDR, we detected 3167 differentially expressed genes, 945 differentially used isoforms and 160 differentially used exons. Isoform switch analysis revealed widespread 3' UTR lengthening associated with cigarette smoking. The lengthening of these 3' UTRs was consistent with alternative usage of distal polyadenylation sites, and these extended 3' UTR regions were significantly enriched with functional sequence elements including microRNA and RNA-protein binding sites. These findings warrant further studies on alternative polyadenylation events as potential biomarkers and novel therapeutic targets for smoking-related diseases.
| S-EPMC8722433 | biostudies-literature
Project description:The prognosis of patients with malignant melanoma has been improved in recent decades due to advancements in immunotherapy. However, a considerable proportion of patients are refractory to treatment, particularly at advanced stages. This underscores the necessity of developing a new strategy to improve it. Alternative polyadenylation (APA), as a marker of crucial posttranscriptional regulation, has emerged as a major new type of epigenetic marker involved in tumorigenesis. However, the potential roles of APA in shaping the tumor microenvironment (TME) are largely unexplored. Herein, we collected two cohorts comprising melanoma patients who received immune checkpoint inhibitor (ICI) immunotherapy to quantify transcriptome-wide discrepancies in APA. We observed a global change in 3'-UTRs between responders and non-responders, which might involve DNA damage response, angiogenesis, PI3K-AKT signaling pathways, etc. Ten putative master APA regulatory factors for those APA events were detected via a network analysis. Notably, we established an immune response-related APA scoring system (IRAPAss), which exhibited a great performance of predicting immunotherapy response in multiple cohorts. Furthermore, we examined the correlation of APA with TME at the single-cell level using four single-cell immune profiles of tumor-infiltrating lymphocytes (TILs), which revealed an overall discrepancy in 3'-UTR length across diverse T cell populations, probably contributing to immunoregulation in melanoma. In conclusion, our study provides a transcriptional landscape of APA implicated in immunoregulation, which might lay the foundation for developing a new strategy for improving immunotherapy response for melanoma patients by targeting APA.
| S-EPMC10931711 | biostudies-literature