Molecular and Clinical Characterization of CCT2 Expression and Prognosis via Large-Scale Transcriptome Profile of Breast Cancer

Molecular chaperones play important roles in regulating various cellular processes and malignant transformation. Expression of some subunits of molecular chaperone CCT/TRiC complex have been reported to be correlated with cancer development and patient survival. However, little is known about the expression and prognostic significance of Chaperonin Containing TCP1 Subunit 2 (CCT2). CCT2 is a gene encoding a molecular chaperone that is a member of the chaperonin containing TCP1 complex (CCT), also known as the TCP1 ring complex (TRiC). Through the Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases, we systematically reviewed a total of 2,994 cases with transcriptome data and analyzed the functional annotation of CCT2 by Gene ontology and KEGG analysis. Univariate and multivariate survival analysis were performed to investigate the prognostic value of CCT2 in breast cancer. We found CCT2 was significantly upregulated in various tumors. In breast cancer, CCT2 expression was significantly upregulated in HER2-positive (HER2+) group, and more malignant group. In addition, we investigated correlations between CCT2 and other CCT members. Interestingly, almost all CCTs expression were positively correlated with each other, but not CCT6B. Survival analysis suggested that CCT2 overexpression was independently associated with worse prognosis of patients with breast cancer, especially in luminal A subtype. In summary, our results revealed that CCT2 might be involved in regulating cell cycle pathway, and independently predicted worse prognosis in breast cancer patients. These findings may expand understanding of potential anti-CCT2 treatments. To our knowledge, this is the largest and most comprehensive study characterizing the expression pattern of CCT2 together with its prognostic values in breast cancer.

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Molecular and clinical characterization of CCT2 expression at transcriptional level via 2994 samples of breast cancer

10.21203/rs.3.rs-44221/v1 ◽

2020 ◽

Author(s):

Qiang Liu ◽

Yihang Qi ◽

Xiangyu Wang ◽

Xiangyi Kong ◽

Yi Fang ◽

...

Keyword(s):

Breast Cancer ◽

Survival Analysis ◽

Molecular Taxonomy ◽

Prognostic Significance ◽

The Cancer Genome Atlas ◽

Transcriptional Level ◽

Breast Cancer Patients ◽

Luminal A ◽

Her2 Positive ◽

Worse Prognosis

Abstract BackgroundMolecular chaperones play important roles in regulating various cellular processes and malignant transformation. Expression of some subunits of molecular chaperonen CCT/TRiC complex have been reported to be correlated with cancer development and patient survival. However, little is known about the expression and prognostic significance of Chaperonin Containing TCP1 Subunit 2 (CCT2), a gene encoding a molecular chaperone that is a member of the chaperonin containing TCP1 complex (CCT), also known as the TCP1 ring complex (TRiC).MethodThrough the Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases, we systematically reviewed a total of 2994 cases with transcriptome data and analyzed the functional annotation of CCT2 by Gene ontology (GO) and KEGG analysis. Univariate and multivariate survival analysis were performed to investigate the prognostic value of CCT2 in breast cancer.ResultsWe found CCT2 was significantly upregulated in various tumors. In breast cancer, CCT2 expression was significantly upregulated in HER2-positive (HER2+) group, and more malignant group. In addition, we investigated correlations between CCT2 and other CCT members. Interestingly, almost all CCTs expression were positively correlated with each other, but not CCT6B. Survival analysis suggested that CCT2 overexpression was independently associated with worse prognosis of patients with breast cancer, especially in luminal A subtype.ConclusionIn summary, our results revealed that CCT2 might be involved in regulating cell cycle pathway, and independently predicted worse prognosis in breast cancer patients. These findings may expand understanding of potential anti-CCT2 treatments. To our knowledge, this is the largest and most comprehensive study characterizing the expression pattern of CCT2 together with its prognostic values in breast cancer.

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TIGIT-related transcriptome profile and its association with tumor immune microenvironment in breast cancer

Bioscience Reports ◽

10.1042/bsr20204340 ◽

2021 ◽

Vol 41 (3) ◽

Author(s):

Qin Zhang ◽

Chaowei Gao ◽

Jianqiang Shao ◽

Zunyi Wang

Keyword(s):

Breast Cancer ◽

Immune Responses ◽

Cancer Immunotherapy ◽

Large Scale ◽

Immune Cell ◽

Molecular Taxonomy ◽

The Cancer Genome Atlas ◽

Immune Checkpoints ◽

Breast Cancer Patients ◽

Transcriptome Profile

Abstract Immune checkpoints are intensively investigated as targets in cancer immunotherapy. T-cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) are recently emerging as a novel promising target in cancer immunotherapy. Herein, we systematically investigated TIGIT-related transcriptome profile and relevant clinical information derived from a total of 2994 breast cancer patients recorded in The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). We uncovered the relationship between TIGIT and major molecular and clinical characteristics in breast cancer. More importantly, we depicted the landscape of associations between TIGIT and other immune cell populations. Gene ontology analyses and Gene Set Variation Analysis (GSVA) of genes correlated with TIGIT revealed that TIGIT were mainly involved in immune responses and inflammatory activities. In summary, TIGIT expression was tightly related to the aggressiveness of breast cancer; TIGIT might manipulate anti-tumor immune responses by impacting not only T cells but also other immune cells. To the best of our knowledge, this is by far the most comprehensive and largest study characterizing the molecular and clinical features of TIGIT in breast cancer through large-scale transcriptome data.

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Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer

Cancers ◽

10.3390/cancers13040833 ◽

2021 ◽

Vol 13 (4) ◽

pp. 833

Author(s):

Jesús Fuentes-Antrás ◽

Ana Lucía Alcaraz-Sanabria ◽

Esther Cabañas Morafraile ◽

María del Mar Noblejas-López ◽

Eva María Galán-Moya ◽

...

Keyword(s):

Breast Cancer ◽

Drug Development ◽

Gene Mutations ◽

Complete Response ◽

Breast Cancer Patients ◽

Clinical Value ◽

Luminal A ◽

Genomic Alterations ◽

Cancer Hallmarks ◽

Worse Prognosis

The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of UBE2T, UBE2C, and BIRC5 conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher UBE2T expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas UBE2C and BIRC5 expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of USP9X and USP7 gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer.

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MiR-100 is a predictor of endocrine responsiveness and prognosis in patients with operable luminal breast cancer

ESMO Open ◽

10.1136/esmoopen-2020-000937 ◽

2020 ◽

Vol 5 (5) ◽

pp. e000937

Author(s):

Annalisa Petrelli ◽

Sara Erika Bellomo ◽

Ivana Sarotto ◽

Franziska Kubatzki ◽

Paola Sgandurra ◽

...

Keyword(s):

Breast Cancer ◽

Prospective Study ◽

Endocrine Therapy ◽

Molecular Subtype ◽

Molecular Taxonomy ◽

Endocrine Resistance ◽

The Cancer Genome Atlas ◽

Response To Treatment ◽

Luminal Breast Cancer ◽

Luminal A

PurposeOverexpression of miR-100 in stem cells derived from basal-like breast cancers causes loss of stemness, induction of luminal breast cancer markers and response to endocrine therapy. We, therefore, explored miR-100 as a novel biomarker in patients with luminal breast cancer.MethodsmiR-100 expression was studied in 90 patients with oestrogen-receptor-positive/human-epidermal growth factor receptor 2-negative breast cancer enrolled in a prospective study of endocrine therapy given either preoperatively, or for the treatment of de novo metastatic disease. Response was defined as a Ki67 ≤2.7% after 21±3 days of treatment. The prognostic role of miR-100 expression was evaluated in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) breast cancer datasets. Additionally, we explored the correlation between miR-100 and the expression its targets reported as being associated with endocrine resistance. Finally, we evaluated whether a signature based on miR-100 and its target genes could predict the luminal A molecular subtype.ResultsBaseline miR-100 was significantly anticorrelated with baseline and post-treatment Ki67 (p<0.001 and 0.004, respectively), and independently associated with response to treatment (OR 3.329, p=0.047). In the METABRIC dataset, high expression of miR-100 identified women with luminal A tumours treated with adjuvant endocrine therapy with improved overall survival (HR 0.55, p<0.001). miR-100 was negatively correlated with PLK1, FOXA1, mTOR and IGF1R expression, potentially explaining its prognostic effect. Finally, a miR-100-based signature developed in patients enrolled in the prospective study outperformed Ki67 alone in predicting the luminal A phenotype.ConclusionsOur findings suggest that miR-100 should be further explored as a biomarker in patients with luminal breast cancer.

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Survival outcomes are associated with genomic instability in luminal breast cancers

PLoS ONE ◽

10.1371/journal.pone.0245042 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0245042

Author(s):

Lydia King ◽

Andrew Flaus ◽

Emma Holian ◽

Aaron Golden

Keyword(s):

Breast Cancer ◽

Genomic Instability ◽

Cancer Survival ◽

Molecular Taxonomy ◽

Gene Signature ◽

Therapeutic Interventions ◽

Survival Outcomes ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Luminal A

Breast cancer is the leading cause of cancer related death among women. Breast cancers are generally diagnosed and treated based on clinical and histopathological features, along with subtype classification determined by the Prosigna Breast Cancer Prognostic Gene Signature Assay (also known as PAM50). Currently the copy number alteration (CNA) landscape of the tumour is not considered. We set out to examine the role of genomic instability (GI) in breast cancer survival since CNAs reflect GI and correlate with survival in other cancers. We focused on the 70% of breast cancers classified as luminal and carried out a comprehensive survival and association analysis using Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data to determine whether CNA Score Quartiles derived from absolute CNA counts are associated with survival. Analysis revealed that patients diagnosed with luminal A breast cancer have a CNA landscape associated with disease specific survival, suggesting that CNA Score can provide a statistically robust prognostic factor. Furthermore, stratification of patients into subtypes based on gene expression has shown that luminal A and B cases overlap, and it is in this region we largely observe luminal A cases with reduced survival outlook. Therefore, luminal A breast cancer patients with quantitatively elevated CNA counts may benefit from more aggressive therapy. This demonstrates how individual genomic landscapes can facilitate personalisation of therapeutic interventions to optimise survival outcomes.

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Dynamic MR imaging as a predictor of prognosis in breast cancer

Spectroscopy An International Journal ◽

10.1155/2006/417637 ◽

2006 ◽

Vol 20 (1) ◽

pp. 19-28

Author(s):

Botond K. Szabó ◽

Maria Kristoffersen-Wiberg

Keyword(s):

Breast Cancer ◽

Mr Imaging ◽

Large Scale ◽

Scientific Evidence ◽

Prognostic Significance ◽

Breast Implants ◽

Breast Cancer Patients ◽

Axillary Metastasis ◽

Complementary Method ◽

The Impact

Contrast-enhanced MR imaging (CE-MRI) has become a widely accepted complementary method for diagnosing breast cancer. It has been suggested for evaluating patients with breast implants, patients at risk of tumour multifocality or recurrence, search for occult primary cancer in presence of axillary metastasis and monitoring the effect of preoperative chemotherapy. The clinical usefulness of MR imaging in patients with increased genetic risk of breast cancer is still under investigation. There is scientific evidence to support the hypothesis that CE-MRI may carry the prognostic significance of angiogenesis, and one of the future indications of this method can be the prognostic evaluation of breast cancer patients by the functional mapping of the angiogenic activity of tumours. On the basis of the promising results of recent reports, further large-scale studies are needed to evaluate the impact of MR parameters on long term overall survival of patients with breast cancer.

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Tumor Microenvironment Subtypes and Immune-Related Signatures for the Prognosis of Breast Cancer

BioMed Research International ◽

10.1155/2021/6650107 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yiqun Han ◽

Jiayu Wang ◽

Binghe Xu

Keyword(s):

Breast Cancer ◽

Clinical Practice ◽

Tumor Microenvironment ◽

Prognostic Model ◽

Cox Regression ◽

Molecular Taxonomy ◽

The Cancer Genome Atlas ◽

Molecular Heterogeneity ◽

Consensus Clustering ◽

Breast Cancer Patients

Objective. To better understand the immune-related heterogeneity of tumor microenvironment (TME) and establish a prognostic model for breast cancer in clinical practice. Methods. For the 2620 breast cancer cases obtained from The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium, the CIBERSORT algorithm was performed to identify the immunological pattern, which underwent consensus clustering to curate TME subtypes, and biological profiles were explored by enrichment analysis. Random forest analysis, least absolute shrinkage, and selection operator analysis, in addition to uni- and multivariate COX regression analyses, were successively employed to precisely select the significant genes with prediction values for the introduction of the prognostic model. Results. Three TME subtypes with distinct molecular and clinical features were identified by an unsupervised clustering approach, of which the molecular heterogeneity could be the result of cell cycle dysfunction and the variation of cytotoxic T lymphocyte activity. A total of 15 significant genes were proposed to construct the prognostic immune-related score system, and a predictive model was established in combination with clinicopathological characteristics for the survival of breast cancer patients. For immunological signatures, proactivity of CD8 T lymphocytes and hyperangiogenesis could be attributed to heterogeneous survival profiles. Conclusions. We developed and validated a prognostic model based on immune-related signatures for breast cancer. This promising model is justified for validation and optimized in future clinical practice.

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Comprehensive Analysis of the Immune and Prognostic Implication of TRIM8 in Breast Cancer

10.21203/rs.3.rs-1152767/v1 ◽

2021 ◽

Author(s):

Cheng Yan ◽

Qingling Liu ◽

Mingkun Nie ◽

Wei Hu ◽

Ruoling Jia

Keyword(s):

Breast Cancer ◽

Cox Regression ◽

Molecular Taxonomy ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Survival Prediction ◽

Mrna Levels ◽

Breast Cancer Patients ◽

Prognostic Signature ◽

Normal Tissues

Abstract Background: Breast cancer remains one of most lethal illnesses for female and the most common malignancies among women, making it important to discover novel biomarkers and therapeutic targets for breast cancer. Immunotherapy has become a promising therapeutic tool for breast cancer. The role of TRIM8 in breast cancer has rarely been reported. Method: Here we identified TRIM8 expression and its potential functions on survival in patients with breast cancer using TCGA (The cancer genome atlas), GEO (Gene expression omnibus) database and METABRIC (Molecular Taxonomy of Breast Cancer International Consortium). Then, TIMER and TISIDB databases were used to investigate the correlations between TRIM8 mRNA levels and immune characteristics. Using stepwise cox regression, we established an immune prognostic signature based on five differentially expression immune-related genes (DE-IRGs). Finally, a nomogram, accompanied by a calibration curve was proposed to predict 1-, 3-, and 5-year survival for breast cancer patients. Results: We found that TRIM8 expression was dramatically lower in breast cancer tissues in comparison with normal tissues. Lower TRIM8 expression was related with worse prognosis in breast cancer. TIMER and TISIDB analysis showed that there were strong correlations between TRIM8 expression and immune characteristics. The receiver operating characteristic (ROC) curve confirmed the good performance in survival prediction, showing good accuracy of the immune prognostic signature. We demonstrated the model usefulness of predictions by nomogram and calibration curves. Our findings indicated that TRIM8 might be a potential link between progression and prognosis survival of breast cancer.Conclusion: This is a comprehensive study to reveal that TRIM8 may serve as a potential prognostic biomarker associating with immune characteristics and provide a novel therapeutic target for the treatment of breast cancer.

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Survival outcomes are associated with genomic instability in luminal breast cancers

10.1101/2020.02.25.20027920 ◽

2020 ◽

Author(s):

Lydia King ◽

Andrew Flaus ◽

Aaron Golden

Keyword(s):

Breast Cancer ◽

Genomic Instability ◽

Statistical Tests ◽

Molecular Taxonomy ◽

Therapeutic Interventions ◽

Survival Outcomes ◽

Breast Cancers ◽

Breast Cancer Patients ◽

Luminal A ◽

Grade 3

AbstractBreast cancer is the leading cause of cancer related death among women. Breast cancers are generally diagnosed and treated based on clinical and histopathological features, along with subtype classification determined by the Prosigna Breast Cancer Prognostic Gene Signature Assay (also known as PAM50). Currently the copy number alteration (CNA) landscape of the tumour is not considered. We set out to examine the role of genomic instability (GI) in breast cancer survival since CNAs reflect GI and correlate with survival in other cancers. We focussed on the 70% of breast cancers classified as luminal and carried out a comprehensive survival and association analysis using Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data to determine whether CNA burden quartiles derived from absolute CNA counts are associated with survival. Luminal A and B patients were stratified by PAM50 subtype and tumour grade and then tested for association with CNA burden using multiple statistical tests. Analysis revealed that patients diagnosed with luminal A grade 3 breast cancer have a CNA landscape associated with disease specific survival, suggesting that these patients could be classified as at-risk. Furthermore, luminal A grade 3 cases largely occupy a region of stratification based on gene expression at the boundary where luminal A and luminal B cases overlap. We conclude that GI reflected by absolute CNA score is a statistically robust prognostic factor for survival in luminal A grade 3 breast cancer. Therefore, luminal A grade 3 breast cancer patients in CNA burden quartiles 3 or 4 may benefit from more aggressive therapy. This demonstrates how individual genomic landscapes can facilitate personalisation of therapeutic interventions to optimise survival outcomes.

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Prognostic significance of KN motif and ankyrin repeat domains 1 (KANK1) in invasive breast cancer

Breast Cancer Research and Treatment ◽

10.1007/s10549-019-05466-8 ◽

2019 ◽

Vol 179 (2) ◽

pp. 349-357 ◽

Cited By ~ 4

Author(s):

Yousif A. Kariri ◽

Chitra Joseph ◽

Sasagu Kurozumi ◽

Michael S. Toss ◽

Mansour Alsaleem ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Invasive Breast Cancer ◽

Tumour Size ◽

Molecular Taxonomy ◽

Prognostic Significance ◽

Ankyrin Repeat ◽

The Cancer Genome Atlas ◽

Lower Grade ◽

Cancer Specific Survival

Abstract Background KN motif and ankyrin repeat domains 1 (KANK1) plays an important role in cytoskeleton maintenance and contributes to the regulation of cell proliferation, adhesion and apoptosis. KANK1 is involved in progression of a variety of solid tumours; however, its role in invasive breast cancer (BC) remains unknown. This study aims to evaluate the clinicopathological and prognostic value of KANK1 expression in operable BC. Methods KANK1 expression was assessed at the transcriptomic level using multiple BC cohorts; the Molecular Taxonomy of BC International Consortium cohort (METABRIC; n = 1980), The Cancer Genome Atlas BC cohort (TCGA; n = 949) and the publicly available BC transcriptomic data hosted by BC Gene-Expression Miner (bc-GenExMiner v4.0) and Kaplan–Meier plotter?. The Nottingham BC cohort (n = 1500) prepared as tissue microarrays was used to assess KANK1 protein expression using immunohistochemistry (IHC). The association between clinicopathological variables and patient outcome was investigated. Results In the METABRIC cohort, high expression of KANK1 mRNA was associated with characteristics of good prognosis including lower grade, absence of lymphovascular invasion and HER2 negativity (all; p < 0.001) and with better outcome [p = 0.006, Hazards ratio, (HR) 0.70, 95% CI 0.54–0.91]. High KANK1 protein expression was correlated with smaller tumour size and HER2 negativity, and better outcome in terms of longer breast cancer-specific survival [p = 0.013, HR 0.7, 95% CI 0.536–0.893] and time to distant metastasis [p = 0.033, HR 0.65, 95% CI 0.51–0.819]. Conclusion These results supported that upregulation of KANK1 works as a tumour suppressor gene in BC and is associated with improved patients’ outcomes.

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