scholarly journals Revealing nuclear receptor hub modules from Basal-like breast cancer expression networks

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252901
Author(s):  
Sharon Nienyun Hsu ◽  
Erika Wong En Hui ◽  
Mengzhen Liu ◽  
Di Wu ◽  
Thomas A. Hughes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Nuclear Receptor ◽  
Drug Targets ◽  
Molecular State ◽  
Network Motifs ◽  
Dependent Manner ◽  
Breast Cancer Patients ◽  
Clustering Method ◽  
Network Modelling ◽  
Basal Like Breast Cancer

Nuclear receptors are a class of transcriptional factors. Together with their co-regulators, they regulate development, homeostasis, and metabolism in a ligand-dependent manner. Their ability to respond to environmental stimuli rapidly makes them versatile cellular components. Their coordinated activities regulate essential pathways in normal physiology and in disease. Due to their complexity, the challenge remains in understanding their direct associations in cancer development. Basal-like breast cancer is an aggressive form of breast cancer that often lacks ER, PR and Her2. The absence of these receptors limits the treatment for patients to the non-selective cytotoxic and cytostatic drugs. To identify potential drug targets it is essential to identify the most important nuclear receptor association network motifs in Basal-like subtype progression. This research aimed to reveal the transcriptional network patterns, in the hope to capture the underlying molecular state driving Basal-like oncogenesis. In this work, we illustrate a multidisciplinary approach of integrating an unsupervised machine learning clustering method with network modelling to reveal unique transcriptional patterns (network motifs) underlying Basal-like breast cancer. The unsupervised clustering method provides a natural stratification of breast cancer patients, revealing the underlying heterogeneity in Basal-like. Identification of gene correlation networks (GCNs) from Basal-like patients in both the TCGA and METABRIC databases revealed three critical transcriptional regulatory constellations that are enriched in Basal-like. These represent critical NR components implicated in Basal-like breast cancer transcription. This approach is easily adaptable and applicable to reveal critical signalling relationships in other diseases.

scholarly journals Tumor suppressive function of Matrin 3 in the basal-like breast cancer

2020 ◽  
Vol 53 (1) ◽  
Author(s):  
Jaehyuk Yang ◽  
Seung Jun Lee ◽  
Yongseok Kwon ◽  
Li Ma ◽  
Jongchan Kim
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Patient Survival ◽  
Apoptotic Cell ◽  
Migration And Invasion ◽  
Breast Cancer Patients ◽  
Human Breast ◽  
Basal Like Breast Cancer ◽  
Tumor Suppressive Function

Abstract Background Basal-like breast cancer (BLBC) or triple-negative breast cancer (TNBC) is an aggressive and highly metastatic subtype of human breast cancer. The present study aimed to elucidate the potential tumor-suppressive function of MATR3, an abundant nuclear protein, in BLBC/TNBC, whose cancer-relevance has not been characterized. Methods We analyzed in vitro tumorigenecity by cell proliferation and soft agar colony formation assays, apoptotic cell death by flow cytometry and Poly (ADP-ribose) polymerase (PARP) cleavage, epithelial-mesenchymal transition (EMT) by checking specific EMT markers with real-time quantitative PCR and in vitro migration and invasion by Boyden Chamber assays. To elucidate the underlying mechanism by which MATR3 functions as a tumor suppressor, we performed Tandem affinity purification followed by mass spectrometry (TAP-MS) and pathway analysis. We also scrutinized MATR3 expression levels in the different subtypes of human breast cancer and the correlation between MATR3 expression and patient survival by bioinformatic analyses of publicly available transcriptome datasets. Results MATR3 suppressed in vitro tumorigenecity, promoted apoptotic cell death and inhibited EMT, migration, and invasion in BLBC/TNBC cells. Various proteins regulating apoptosis were identified as MATR3-binding proteins, and YAP/TAZ pathway was suppressed by MATR3. MATR3 expression was inversely correlated with the aggressive and metastatic nature of breast cancer. Moreover, high expression levels of MATR3 were associated with a good prognosis of breast cancer patients. Conclusions Our data demonstrate that MATR3 functions as a putative tumor suppressor in BLBC/TNBC cells. Also, MATR3 potentially plays a role as a biomarker in predicting chemotherapy-sensitivity and patient survival in breast cancer patients.

Genomic mapping to identify mutations in RYR2 and AHNAK in basal-like breast tumors expressing PD-L1.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1027-1027
Author(s):  
Francisco J Cimas ◽  
Aránzazu Manzano ◽  
Mariona Baliu Piqué ◽  
Pedro Perez ◽  
Ádám Nagy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Cell ◽  
Breast Tumors ◽  
Good Prognosis ◽  
Clinical Activity ◽  
Breast Cancer Patients ◽  
L1 Data ◽  
Transcriptomic Signature ◽  
Basal Like Breast Cancer ◽  
Tcga Dataset

1027 Background: Basal-like breast cancer is a specific subtype of breast tumors with limited therapeutic options. Although treatment with the anti-PD-L1 antibody atezolizumab has recently shown clinical activity in this setting, not all patients do respond even expressing high levels of PD-L1. In the present article we explored the presence of mutations in breast cancer tumors with high expression of PD1 and PD-L1 with the aim to identify molecular correlates associated with outcome. Methods: We used RNA-seq and mutational data from 971 breast cancer patients using the TCGA dataset, to identify mutations in patients with high levels of PD1 and PD-L1. Data analysis was performed using DESeq R and MAFTools Bioconductor packages. Transcriptomic signatures from the identified mutations were associated with outcome using the Kapplan-Meyer Plotter tool. We correlated the identified transcripts with immune populations using TIMER online tool and correlation between genes with Cancertool online platform. Results: We identified co-occurrent mutations in RYR2 and AHNAK in 8% and 5% of basal like tumors, respectively, in patients with high levels of PD1 and PD-1. The transcriptomic signature of these mutations conferred good prognosis for relapse free survival (RFS) and overall survival (OS). CXCL9 for RYR2 and GBP5, C1QA, IL2RG, CSF2RB and IDO1 for AHNAK were the most relevant genes identified in these signatures. Expression of CXCL9, GBP5, IL2RG and IDO1 correlated with the presence of immune cell populations mainly dendritic cells. This signature, including CXCL9, GBP5, C1QA, IL2RG, CSF2RB and IDO1 classified patients with favorable RFS (HR 0.27 CI 0.2-0.30; p = 1.1e-16) and OS (HR 0.18 CI 0.09-0.34; p = 6.8e-9). This signature showed a stronger prediction capacity compared with already described immunologic signatures. Finally we identify that LAG3 was the only gene commonly present in both signatures and correlated positively with the expression of PD1 and PD-L1. Conclusions: We describe two novel mutations which transcriptomic signatures associated with favorable outcome in basal-like tumors that express elevated levels of PD1 and PD-L1. Future studies should be performed to confirm the role of these mutations and signatures in relation with clinical activity of PD1/PD-L1 inhibitors.

scholarly journals FEATURES OF LYMPHOCYTES IN THE BLOOD IN PATIENTS WITH BASAL-LIKE BREAST CANCER SOUTH-EAST UKRAINE

2016 ◽  
Author(s):  
T. Yu. Pohorila ◽  
N. F. Shchurov ◽  
S. M. Pashchenko
Keyword(s):  
Breast Cancer ◽  
Peripheral Blood ◽  
Antitumor Immunity ◽  
Morphological Characteristics ◽  
Peripheral Blood Lymphocytes ◽  
Comprehensive Treatment ◽  
Breast Cancer Patients ◽  
Blood Lymphocytes ◽  
Before And After ◽  
Basal Like Breast Cancer

Lymphocytes are important in antitumor immunity. Therefore, the estimate of the magnitude of lymphocytes, could be used to determine the protective capabilities of the organism basal-like breast cancer patients. The purpose of the study: building a morphological features peripheral blood lymphocytes of patients with basal-like breast cancer South-East Ukraine, receiving comprehensive chemoradiotherapy. It was found that treatment BLT changes the structure of peripheral blood lymphocytes. After the comprehensive treatment of peripheral blood lymphocytes of patients significantly increased in size, they decreased nuclear-cytoplasmic ratio. For definitions immune status of patients basal-like breast cancer no small role played by morphological characteristics of lymphocytes in the peripheral blood before and after complex treatment.

scholarly journals A Precision Medicine Approach to Metabolic Therapy for Breast Cancer in Mice

2021 ◽  
Author(s):  
Ngozi D Akingbesote ◽  
Aaron Norman ◽  
Wanling Zhu ◽  
Alexandra A Halberstam ◽  
Xinyi Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Precision Medicine ◽  
Cancer Patients ◽  
Insulin Signaling ◽  
Breast Tumors ◽  
Sglt2 Inhibitors ◽  
Dependent Manner ◽  
Breast Cancer Patients ◽  
Metabolic Therapy ◽  
Response To Chemotherapy

Increasing evidence highlights the possibility for approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic therapies and have recently been highlighted as a novel therapeutic approach to breast cancer. To our knowledge, however, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach to combining metabolic therapy with standard of care therapy for this devastating disease. In this study, we combine the SGLT2 inhibitor dapagliflozin with paclitaxel chemotherapy in both lean and obese mice. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival in an insulin-dependent manner in some but not all breast tumors. Our data find a genetic signature for breast tumors most likely to respond to dapagliflozin in combination with paclitaxel. Tumors driven by mutations upstream of canonical insulin signaling pathways are likely to respond to such treatment, whereas tumors driven by mutations downstream of canonical insulin signaling are not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that breast cancer patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach. A clinical trial is currently in preparation, with an application recently submitted for Yale Human Investigations Committee approval, to test this hypothesis in breast cancer patients.

scholarly journals Inhibition of UGT8 suppresses basal-like breast cancer progression by attenuating sulfatide–αVβ5 axis

2018 ◽  
Vol 215 (6) ◽  
pp. 1679-1692 ◽  
Author(s):  
Qianhua Cao ◽  
Xingyu Chen ◽  
Xuebiao Wu ◽  
Ruocen Liao ◽  
Panpan Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Biosynthetic Pathway ◽  
Treatment Options ◽  
Prognostic Indicator ◽  
Inhibitory Effect ◽  
Breast Cancer Patients ◽  
Elevated Expression ◽  
Basal Like Breast Cancer ◽  
Pharmacologic Inhibition

Basal-like breast cancer (BLBC) is associated with a poor clinical outcome as a result of the few treatment options and poor therapeutic response. Here, we report that elevated expression of urine diphosphate–galactose ceramide galactosyltransferase (UGT8) specifically occurs in BLBC and predicts poor prognosis in breast cancer patients. UGT8 expression is transcriptionally up-regulated by Sox10, triggering the sulfatide biosynthetic pathway; increased sulfatide activates integrin αVβ5-mediated signaling that contributes to BLBC progression. UGT8 expression promotes, whereas UGT8 knockdown suppresses tumorigenicity and metastasis. Importantly, we identify that zoledronic acid (ZA), a marketed drug for treating osteoporosis and bone metastasis, is a direct inhibitor of UGT8, which blocks the sulfatide biosynthetic pathway. Significantly, a clinically achievable dosage of ZA exhibits apparent inhibitory effect on migration, invasion, and lung metastasis of BLBC cells. Together, our study suggests that UGT8 is a potential prognostic indicator and druggable target of BLBC and that pharmacologic inhibition of UGT8 by ZA offers a promising opportunity for treating this challenging disease.

scholarly journals Evaluating the Association between CCR5delta32 Polymorphism (rs333) and the Risk of Breast Cancer in a Cohort of Iranian Population

2021 ◽  
Author(s):  
Amir TAJBAKHSH ◽  
Zahra FARJAMI ◽  
Abolfazl NESAEI-BAJESTANI ◽  
Fahimeh AFZALJAVAN ◽  
Mahdi RIVANDI ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Tumour ◽  
Dependent Manner ◽  
Breast Cancer Patients ◽  
North East ◽  
East Of Iran ◽  
Hardy Weinberg Equilibrium ◽  
Cc Chemokine Receptor 5 ◽  
And Control ◽  
Control Samples

Background: CC chemokine receptor 5 (CCR5) is introduced as an immune response modulator. The activity of CCR5 influences breast tumour development in a p53-dependent manner. This study aimed to investigate the frequency of CCR5delta32 and its association with the risk of breast cancer in 1038 blood samples in North East of Iran. Methods: In this case-control study, we genotyped 570 control samples and 468 breast cancer patients by a gel electrophoresis-based gap-polymerase chain reaction (gap-PCR) method Mashhad, Iran. The data were analyzed using the SPSS software. Results: Of 570 controls included, 542 (95.09%) had CCR5delta32 wild/wild (W/W) genotype, 28 samples (4.91%) had CCR5delta32 wild/deletion (W/D) genotype and none of them were CCR5delta32 deletion/deletion (D/D) genotype (0%). While 428 samples of patients (91.45%) had CCR5delta32 W/W genotype, 40 samples (8.55%) had CCR5delta32 W/D and CCR5delta32 D/D homozygous was nil (0%) amongst cases. All samples were in the Hardy–Weinberg equilibrium (P>0.05). According to the allele frequency, D allele, as a risky allele, in the cases was more than the control samples (0.0427 vs 0.0245, respectively) (P=0.0206). Hence, W/D genotype may confer a risk effect (OR=1.77, CI: 1.09-2.90; P=0.0206) compared with WW genotype between case and control groups. Conclusion: There is a statistically significant association between CCR5W/D and breast cancer risk. CCR5 may be regarded as a target for the prevention of breast cancer in certain conditions such as interaction with p53 variants, which remains to be further investigated.

scholarly journals Integrative Analysis of Response to Tamoxifen Treatment in ER-Positive Breast Cancer Using GWAS Information and Transcription Profiling

2012 ◽  
Vol 6 ◽  
pp. BCBCR.S8652 ◽  
Author(s):  
Chindo Hicks ◽  
Ranjit Kumar ◽  
Antonio Pannuti ◽  
Lucio Miele
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Drug Targets ◽  
Association Studies ◽  
Biological Pathways ◽  
Tamoxifen Treatment ◽  
Genome Wide Association Studies ◽  
Breast Cancer Patients ◽  
Variable Response ◽  
Transcription Profiling

Variable response and resistance to tamoxifen treatment in breast cancer patients remains a major clinical problem. To determine whether genes and biological pathways containing SNPs associated with risk for breast cancer are dysregulated in response to tamoxifen treatment, we performed analysis combining information from 43 genome-wide association studies with gene expression data from 298 ER+ breast cancer patients treated with tamoxifen and 125 ER+ controls. We identified 95 genes which distinguished tamoxifen treated patients from controls. Additionally, we identified 54 genes which stratified tamoxifen treated patients into two distinct groups. We identified biological pathways containing SNPs associated with risk for breast cancer, which were dysregulated in response to tamoxifen treatment. Key pathways identified included the apoptosis, P53, NFkB, DNA repair and cell cycle pathways. Combining GWAS with transcription profiling provides a unified approach for associating GWAS findings with response to drug treatment and identification of potential drug targets.

Nuclear Receptor Coactivator 5 is Correlated with Progression in Breast Carcinoma

2021 ◽  
Vol 21 ◽  
Author(s):  
Erjie Xia ◽  
Wenjing Hu ◽  
Adheesh Bhandari ◽  
Namita Sindan ◽  
Duping Huang
Keyword(s):  
Breast Cancer ◽  
Logistic Regression ◽  
Nuclear Receptor ◽  
Clinical Stage ◽  
Multivariate Logistic Regression Analysis ◽  
The Cancer Genome Atlas ◽  
Rank Test ◽  
Breast Cancer Patients ◽  
Multivariate Logistic Regression ◽  
Er Status

Background: Breast cancer (BC) is increasingly becoming the primary reason for death in women, which sounded the alarm. Thus, finding a novel management target for BC is imminent. Methods: The data of gene expression and clinicopathological characteristics were downloaded from The Cancer Genome Atlas (TCGA). The expression of nuclear receptor co-activator 5 (NCOA5) in 35 paired breast cancer and adjacent tissues were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Univariate and Multivariate logistic regression methodology was applied to analyze the prognostic factors for lymph node metastasis (LNM). Based on the status of breast cancer-relative receptors, patients were distributed in six groups, then the Kaplan-Meier survival analysis with log-rank test was applied to investigate the involvement among the expression of NCOA5 and overall survival (OS). Results: The expression of NCOA5 in BC was greater than normal tissues when comparing the data from TCGA. This result had also been verified in our local cohort. The expression of NCOA5 was closely related to LNM, Estrogen receptor(ER) status, progesterone receptor(PR) status. The consequence of Multivariate logistic regression analysis showed that the expression of NCOA5,tumor size, ER status and clinical stage significantly associated to LN. Moreover, subgroup analyses showed that high expression of NCOA5 is an independent risk factor for OS in patients who were in ER (+) or PR (+) or maybe human epidermal growth factor receptor-2(Her-2) positive status. Conclusion: NCOA5 was significantly correlated with LNM in BC. Meanwhile, the expression of NOCA5 could predict the OS time, especially in breast cancer patients whose status of hormone receptor was positive. NCOA5 may act as a promising treatment target to shortening the treatment period and improving the prognosis of ER (+) breast cancer.

scholarly journals Nuclear receptor co-activators and HER-2/neu are upregulated in breast cancer patients during neo-adjuvant treatment with aromatase inhibitors

2009 ◽  
Vol 101 (8) ◽  
pp. 1253-1260 ◽  
Author(s):  
M Hauglid Flågeng ◽  
L L Haugan Moi ◽  
J M Dixon ◽  
J Geisler ◽  
E A Lien ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Nuclear Receptor ◽  
Aromatase Inhibitors ◽  
Adjuvant Treatment ◽  
Breast Cancer Patients ◽  
Her 2
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