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

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.

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

2021 ◽  
Vol 11 ◽  
Author(s):  
Qiang Liu ◽  
Yihang Qi ◽  
Xiangyi Kong ◽  
Xiangyu Wang ◽  
Wenxiang Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Survival Analysis ◽  
Molecular Chaperone ◽  
Large Scale ◽  
Molecular Taxonomy ◽  
Prognostic Significance ◽  
The Cancer Genome Atlas ◽  
Breast Cancer Patients ◽  
Luminal A ◽  
Worse Prognosis

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.

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

Cancers ◽  
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.

Prognostic subset of metastatic and non-metastatic luminal B breast cancer (LBBC) subtype based on Ki67 index.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12570-e12570
Author(s):  
Lalnun Puii ◽  
Lalram Sangi ◽  
Hrishi Varayathu ◽  
Samuel Luke Koramati ◽  
Beulah Elsa Thomas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Disease ◽  
Ki67 Index ◽  
Breast Cancer Patients ◽  
Luminal A ◽  
Her2 Positive ◽  
Ki 67 ◽  
Luminal B ◽  
Therapeutic Implications ◽  
Significant Difference

e12570 Background: Gene expression profiling for breast cancer has classified ER positive subtype into luminal A and luminal B. Luminal B breast cancer (LBBC) have a higher proliferation and poorer prognosis than luminal A tumors. Ki-67 index is the commonly used proliferation marker in breast cancer; however Ki67 expression can also be used to identify a subset of patients among LB with a favorable prognosis. This study attempts to verify this subset of LBBC patients based on DFS and PFS in non-metastatic and metastatic patients respectively. Methods: We retrospectively analyzed 80 IDC breast cancer patients diagnosed in 2013-2016 with complete follow-up till January-2021. We defined LBBC as ER+, PR+ or PR- , HER2+ or HER2- with a Ki67 index >20%. PFS was considered as the endpoint in patients presenting with metastatic disease whereas DFS was used in non-metastatic disease. The cut-off for ki67 was calculated using an X-tile plot (version 3.6.1, Yale University) by dividing Ki67 data into two populations: low and high, with randomized 1:1 “training” and “validation” cohorts. Results: Median age was 51.5 years. 18.7% (n=15) presented with metastasis at the time of diagnosis and their overall median PFS was found to be 25.8 months. The incidence of HER2 positive LBBC was found to be 15% (n=12) and none of them were found to be presented with metastasis. Survival and frequency of various sub groups in our study are enlisted in the given table. We estimated a Ki67 cut-off of 30% in patients with upfront metastatic disease and PFS was found to be higher in <30% compared to a Ki67 index >30% (38.9 months vs 19.7 months, p-0.002). Overall median DFS was not achieved in non-metastatic group (Mean DFS: 64.7 months) where as a statistically significant difference was observed in the survival of HER2 positive (median DFS: 53.5 months, mean DFS: 50.9) than HER2 negative patients (median DFS not achieved, mean: 66.97 months) ( p-0.021). We obtained a Ki67 cut-off of 32% in non- metastatic group and mean DFS was found to be higher in Ki67<32% (69 months) compared to Ki67>32% (61.4 months), however it failed to exhibit a statistically significant relationship ( p-0.373). Conclusions: Our study indicates that a subset of patients exists within metastatic and non-metastatic LBBC with differing prognosis based on Ki67. Larger studies are further required to confirm the findings and therapeutic implications.[Table: see text]

scholarly journals Extracellular Matrix Features Discriminate Aggressive HER2-Positive Breast Cancer Patients Who Benefit from Trastuzumab Treatment

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 434
Author(s):  
Ilona Rybinska ◽  
Marco Sandri ◽  
Francesca Bianchi ◽  
Rosaria Orlandi ◽  
Loris De Cecco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Extracellular Matrix ◽  
Gene Expression Pattern ◽  
Response To Therapy ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Adjuvant Trastuzumab ◽  
Trastuzumab Treatment ◽  
Worse Prognosis

We previously identified an extracellular matrix (ECM) gene expression pattern in breast cancer (BC), called ECM3, characterized by a high expression of genes encoding structural ECM proteins. Since ECM is reportedly implicated in response to therapy of BCs, the aim of this work is to investigate the prognostic and predictive value of ECM3 molecular classification in HER2-positive BCs. ECM3 resulted in a robust cluster that identified a subset of 25–37% of HER2-positive tumors with molecular aggressive features. ECM3 was significantly associated with worse prognosis in two datasets of HER2-positive BCs untreated with adjuvant therapy. Analyses carried out on two of our cohorts of patients treated or not with adjuvant trastuzumab showed association of ECM3 with worse prognosis only in patients not treated with trastuzumab. Moreover, investigating a dataset that includes gene profile data of tumors treated with neoadjuvant trastuzumab plus chemotherapy or chemotherapy alone, ECM3 was associated with increased pathological complete response if treated with trastuzumab. In the in vivo experiments, increased diffusion and trastuzumab activity were found in tumors derived from injection of HER2-positive cells with Matrigel that creates an ECM-rich tumor environment. Taken together, these results indicate that HER2-positive BCs classified as ECM3 have an aggressive phenotype but they are sensitive to trastuzumab treatment.

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

ESMO Open ◽  
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.

scholarly journals Elevated microRNA-125b levels predict a worse prognosis in HER2-positive breast cancer patients

2016 ◽  
Vol 13 (2) ◽  
pp. 867-874 ◽  
Author(s):  
Yanwei Luo ◽  
Xinye Wang ◽  
Weihong Niu ◽  
Heran Wang ◽  
Qiuyuan Wen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Worse Prognosis ◽  
Positive Breast Cancer

scholarly journals Survival outcomes are associated with genomic instability in luminal breast cancers

PLoS ONE ◽  
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.

scholarly journals Comparison of Clinico-Pathological Presentations of Triple-Negative versus Triple-Positive and HER2 Iraqi Breast Cancer Patients

2019 ◽  
Vol 7 (21) ◽  
pp. 3534-3539
Author(s):  
Nada A. S. Alwan ◽  
Furat N. Tawfeeq
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Molecular Subtype ◽  
Clinical Stage ◽  
Lymph Node Involvement ◽  
Breast Cancer Patients ◽  
Luminal A ◽  
Her2 Positive ◽  
Cancer Subtypes ◽  
Significant Difference

BACKGROUND: Breast cancer remains the most common malignancy among the Iraqi population. Affected patients exhibit different clinical behaviours according to the molecular subtypes of the tumour. AIM: To identify the clinical and pathological presentations of the Iraqi breast cancer subtypes identified by Estrogen receptors (ER), Progesterone receptors (PR) and HER2 expressions. PATIENTS AND METHODS: The present study comprised 486 Iraqi female patients diagnosed with breast cancer. ER, PR and HER2 contents of the primary tumours were assessed through immunohistochemical staining; classifying the patients into five different groups: Triple Negative (ER/PR negative/HER2 negative), Triple Positive (ER/PR positive/HER2 positive), Luminal A (ER/PR positive/HER2 negative), HER2 enriched ((ER/PR negative/HER2 positive) and all other subtypes. RESULTS: The major registered subtype was the Luminal A which was encountered in 230 patients (47.3%), followed by the Triple Negative (14.6%), Triple Positive (13.6%) and HER2 Enriched (11.5%). Patients exhibiting the Triple Negative subtype were significantly younger than the rest of the groups and presented with larger size tumours. A significant difference in the distribution of the breast cancer stages was displayed (p < 0.05); the most advanced were noted among those with HER2 enriched tumours who exhibited the highest frequency of poorly differentiated carcinomas and lymph node involvement. CONCLUSION: The most significant variations in the clinicopathological presentations were observed in the age and clinical stage of the patients at diagnosis. Adoption of breast cancer molecular subtype classification in countries with limited resources could serve as a valuable prognostic marker in the management of aggressive forms of the disease.

scholarly journals Neoadjuvant Model as a Platform for Research in Breast Cancer and Novel Targets under Development in this Field

Breast Care ◽  
2018 ◽  
Vol 13 (4) ◽  
pp. 251-262 ◽  
Author(s):  
Santiago Escrivá-de-Romaní ◽  
Miriam Arumí ◽  
Esther Zamora ◽  
Meritxell Bellet
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Subtype ◽  
Pathologic Complete Response ◽  
Surrogate Marker ◽  
Prognostic Index ◽  
Complete Response ◽  
Breast Cancer Patients ◽  
Luminal A ◽  
Neoadjuvant Endocrine Therapy ◽  
Her2 Positive

For decades, the neoadjuvant setting has provided a useful scenario for research in breast cancer. Historically, neoadjuvant clinical trials, either hormone therapy-based or chemotherapy-based, have tried to recapitulate the results of their counterpart adjuvant studies, but with smaller patient numbers, more rapid outcomes (clinical response and/or pathologic complete response (pCR)), together with additional biologic information. As for neoadjuvant chemotherapy trials, the increase in pCR rates has been recently accepted as an appropriate surrogate marker to accelerate drug approval in high-risk breast cancer patients. In this setting, with the exception of luminal A tumors, pCR has been associated with improved long-term outcomes, particularly when the analysis is based on specific trials for each breast cancer subtype. For luminal tumors receiving neoadjuvant endocrine therapy, Ki67 at 2-4 weeks and the preoperative endocrine prognostic index score are the most accepted intermediate markers of efficacy, which will be validated in ongoing larger trials. In this review, we describe the different neoadjuvant designs: from the classical randomized trials in which treatment is delivered for 6 or more months to short non-therapeutic presurgical studies lasting just 2 or 3 weeks. We also review the main neoadjuvant trials, either ongoing or completed, for luminal, triple-negative, and HER2-positive breast cancer. The translational effort and research of biomarkers conducted in these studies will be particularly addressed.

scholarly journals VGLL1 expression is associated with a triple-negative basal-like phenotype in breast cancer

2014 ◽  
Vol 21 (4) ◽  
pp. 587-599 ◽  
Author(s):  
María Ángeles Castilla ◽  
María Ángeles López-García ◽  
María Reina Atienza ◽  
Juan Manuel Rosa-Rosa ◽  
Juan Díaz-Martín ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Tissue Microarrays ◽  
The Cancer Genome Atlas ◽  
Luminal Progenitor ◽  
Breast Carcinomas ◽  
Luminal A ◽  
Her2 Positive ◽  
Cancer Subtypes ◽  
Grade 3

Vestigial-like 1 (VGLL1) is a poorly characterized gene encoding a transcriptional co-activator structurally homologous toTAZandYAPthat modulates the Hippo pathway inDrosophila. In this study, we examined the expression ofVGLL1and its intronic miRNA, miR-934, in breast cancer.VGLL1and miR-934 expression miRNA profiling was carried out on frozen samples of grade 3 invasive ductal carcinomas. VGLL1 protein was also examined in 433 sporadic andBRCA1-associated breast carcinomas on tissue microarrays. RNA-seq data from The Cancer Genome Atlas (TCGA) was used to confirm differences inVGLL1and miR-934 expression in different breast cancer subtypes, and to correlate their expression with that of other genes and miRNAs. Of 28 miRNAs differentially expressed in estrogen receptor (ER)-positive and ER-negative grade 3 breast carcinomas, miR-934 was most strongly upregulated in ER-negative carcinomas, and its expression was correlated with that ofVGLL1. NuclearVGLL1expression was observed in 13% of sporadic breast carcinomas, and whileVGLL1was only occasionally found in luminal A (0.70%) and B (5.60%) carcinomas, it was often expressed in HER2-positive (17%), triple-negative (TN) breast carcinomas (>40%) andBRCA1-associated TN carcinomas (>50%). These findings were confirmed in the TCGA dataset, which revealed positive associations with luminal progenitor genes (GABRP,SLC6A14,FOXC1,PROM1, andBBOX1) and strong negative correlations with ER-associated genes (ESR1,C6ORF211,GATA3, andFOXA1). Moreover,VGLL1expression was associated with reduced overall survival. In conclusion,VGLL1and miR-934 are mainly expressed in sporadic andBRCA1-associated TN basal-like breast carcinomas, and their coordinated expression, at least partially mediated by the direct modulation ofESR1, might be involved in the maintenance of a luminal progenitor phenotype.

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