scholarly journals High BRCA1 gene expression increases the risk of early distant metastasis in ER+ breast cancers

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Hui-Ju Chang ◽  
Ueng-Cheng Yang ◽  
Mei-Yu Lai ◽  
Chen-Hsin Chen ◽  
Yang-Cheng Fann
Keyword(s):  
Gene Expression ◽  
Distant Metastasis ◽  
Brca1 Gene ◽  
Estrogen Signaling ◽  
Tamoxifen Treatment ◽  
Testable Hypothesis ◽  
Marker Genes ◽  
Proliferation Marker ◽  
Breast Cancers ◽  
Brca1 Protein

AbstractAlthough the function of the BRCA1 gene has been extensively studied, the relationship between BRCA1 gene expression and tumor aggressiveness remains controversial in sporadic breast cancers. Because the BRCA1 protein is known to regulate estrogen signaling, we selected microarray data of ER+ breast cancers from the GEO public repository to resolve previous conflicting findings. The BRCA1 gene expression level in highly proliferative luminal B tumors was shown to be higher than that in luminal A tumors. Survival analysis using a cure model indicated that patients of early ER+ breast cancers with high BRCA1 expression developed rapid distant metastasis. In addition, the proliferation marker genes MKI67 and PCNA, which are characteristic of aggressive tumors, were also highly expressed in patients with high BRCA1 expression. The associations among high BRCA1 expression, high proliferation marker expression, and high risk of distant metastasis emerged in independent datasets, regardless of tamoxifen treatment. Tamoxifen therapy could improve the metastasis-free fraction of high BRCA1 expression patients. Our findings link BRCA1 expression with proliferation and possibly distant metastasis via the ER signaling pathway. We propose a testable hypothesis based on these consistent results and offer an interpretation for our reported associations.

scholarly journals High BRCA1 Gene Expression Increases the Risk of Early Onset Distant Metastasis in ER+ Breast Cancers

2020 ◽  
Author(s):  
Hui-Ju Chang ◽  
Ueng-Cheng Yang ◽  
Mei-Yu Lai ◽  
Chen-Hsin Chen ◽  
Yang-Cheng Fann
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Tumor Cells ◽  
Distant Metastasis ◽  
Early Onset ◽  
Onset Time ◽  
Transcript Level ◽  
Breast Cancers ◽  
Data Set ◽  
Brca1 Protein

Abstract BackgroundMore than 30% of ER+ breast cancer patients developed distant metastasis after adjuvant tamoxifen therapy. It has been shown that decreased BRCA1 protein function confers anti-estrogen “resistance.” Since the functional status of BRCA1 protein auto-regulates its own gene expression, BRCA1 transcript level should possibly be used to assess its active protein levels. Thus, it is interesting to explore the potential links between BRCA1 gene expression status and the prognosis of ER+ breast tumors.MethodsEarly-staged ER+ Breast cancer microarray samples were selected from the NCBI Gene Expression Omnibus (GEO) database. The aggressiveness of these tumors was evaluated based on molecular subtypes or patients’ distant metastasis-free survival (DMFS) time found in associated GEO datasets. In survival analysis, the optimal threshold to define high and low transcript levels was assessed by the logistic-accelerated failure time mixture regression model in a pooled data set, which simultaneously envisages the lifetime risk of distant metastasis and the distribution of the DMFS time from the surgery of a patient susceptible to distant metastasis. ResultsOn the basis of molecular subtyping, the relatively aggressive Luminal B tumor cells expressed significantly more BRCA1 transcripts than the less aggressive Luminal A tumor cells. This observation was supported by DMFS time analysis. When the upper 10% of the high BRCA1 expression patients was compared with the rest of the patients, the result was quite drastic. In patients susceptible to distant metastasis, the median onset time of distant metastasis for high BRCA1 expression group (2.2 years) was about one-fifth of the BRCA1 low expression group (10.5 years).ConclusionsHigh BRCA1 transcript level does not increase the incidence of distant metastasis, but increases the risk of early onset distant metastasis in ER+ breast cancers. As new therapeutic drugs have been developed for tumors with BRCA function loss, our findings suggest that BRCA1 gene expression test not only is useful for predicting patients’ outcome but also can be used in treatment decision.

scholarly journals Epigenetic Activation of BRCA1 by Genistein In Vivo and Triple Negative Breast Cancer Cells Linked to Antagonism toward Aryl Hydrocarbon Receptor

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2559 ◽  
Author(s):  
Donovan ◽  
Selmin ◽  
Doetschman ◽  
Romagnolo
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Triple Negative ◽  
Brca1 Gene ◽  
Cpg Methylation ◽  
Breast Cancers ◽  
Mcf7 Cells ◽  
Brca1 Protein ◽  
Protein Levels ◽  
Aryl Hydrocarbon

Triple negative breast cancers (TNBC) are the most aggressive and lethal breast cancers (BC). The aryl hydrocarbon receptor (AHR) is often overexpressed in TNBC, and its activation results in the epigenetic silencing of BRCA1, which is a necessary factor for the transcriptional activation of estrogen receptor (ER)α. The dietary isoflavone genistein (GEN) modulates BRCA1 CpG methylation in BC cells. The purpose of this study was to investigate the effect of GEN on BRCA1 epigenetic regulation and AHR activity in vivo and TNBC cells. Mice were administered a control or GEN-enriched (4 and 10 ppm) diet from gestation through post-natal day 50. Mammary tissue was analyzed for changes in BRCA1 regulation and AhR activity. TNBC cells with constitutively hypermethylated BRCA1 (HCC38) and MCF7 cells were used. Protein levels and mRNA expression were measured by Western blot and real-time PCR, respectively. BRCA1 promoter occupancy and CpG methylation were analyzed by chromatin immunoprecipitation and methylation-specific PCR, respectively. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. GEN administered in the diet dose-dependently decreased basal Brca1 methylation and AHR activity in the mammary gland of adult mice. HCC38 cells were found to overexpress constitutively active AHR in parallel with BRCA1 hypermethylation. The treatment of HCC38 cells with GEN upregulated BRCA1 protein levels, which was attributable to decreased CpG methylation and AHR binding at BRCA1 exon 1a. In MCF7 cells, GEN prevented the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-dependent localization of AHR at the BRCA1 gene. These effects were consistent with those elicited by control AHR antagonists galangin (GAL), CH-223191, and α-naphthoflavone. The pre-treatment with GEN sensitized HCC38 cells to the antiproliferative effects of 4-hydroxytamoxifen. We conclude that the dietary compound GEN may be effective for the prevention and reversal of AHR-dependent BRCA1 hypermethylation, and the restoration of ERα-mediated response, thus imparting the sensitivity of TNBC to antiestrogen therapy.

scholarly journals Negative Regulation of BRCA1 Gene Expression by HMGA1 Proteins Accounts for the Reduced BRCA1 Protein Levels in Sporadic Breast Carcinoma

2003 ◽  
Vol 23 (7) ◽  
pp. 2225-2238 ◽  
Author(s):  
Gustavo Baldassarre ◽  
Sabrina Battista ◽  
Barbara Belletti ◽  
Sanjay Thakur ◽  
Francesca Pentimalli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Breast Carcinoma ◽  
Es Cells ◽  
Embryonic Stem ◽  
Brca1 Gene ◽  
Brca1 Protein ◽  
Protein Levels ◽  
Sporadic Breast Carcinoma

ABSTRACT A drastic reduction in BRCA1 gene expression is a characteristic feature of aggressive sporadic breast carcinoma. However, the mechanisms underlying BRCA1 downregulation in breast cancer are not well understood. Here we report that both in vitro and in vivo HMGA1b protein binds to and inhibits the activity of both human and mouse BRCA1 promoters. Consistently, murine embryonic stem (ES) cells with the Hmga1 gene deleted display higher Brca1 mRNA and protein levels than do wild-type ES cells. Stable transfection of MCF-7 cells with the HMGA1b cDNA results in a decrease of BRCA1 gene expression and in a lack of BRCA1 induction after estrogen treatment. Finally, we found an inverse correlation between HMGA1 and BRCA1 mRNA and protein expression in human mammary carcinoma cell lines and tissues. These data indicate that HMGA1 proteins are involved in transcriptional regulation of the BRCA1 gene, and their overexpression may have a role in BRCA1 downregulation observed in aggressive mammary carcinomas.

Genotype and phenotype in hereditary and sporadic breast cancers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10538-10538
Author(s):  
G. Giorgetti ◽  
E. Galizia ◽  
F. Bianchi ◽  
C. Ferretti ◽  
F. Corradini ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Cpg Island ◽  
Direct Sequencing ◽  
Gene Expression Signature ◽  
Brca1 Gene ◽  
Promoter Hypermethylation ◽  
Germline Mutations ◽  
Breast Cancers ◽  
Brca1 Protein ◽  
Brca1 Promoter

10538 Background: BRCA1 protein is involved in distinct DNA-repair processes. Germline mutations in BRCA1 gene confer cancer susceptibility. A frequent mechanism for epigenetic inactivation is hypermethylation of the CpG island in promoters of tumours suppressor genes. BRCA1 promoter hypermethylation has been found in a variable percentage of breast cancers (15–30%). BRCA1-associated breast cancers are usually high-grade, poorly differentiated and stain negative for HER2/neu, oestrogen and progesterone receptors (ER, PgR). Many studies have shown that hereditary BRCA1 and basal-like sporadic breast tumours have a similar phenotype and gene expression signature. Methods: By clinical criteria, 223 patients were selected and, for each patient, the probability to carry a BRCA1 mutation was calculated using the software BRCAPRO and Manchester Score System. All patients were studied by direct sequencing and MLPA of BRCA1 Open Reading Frames (ORFs). Thirty sporadic breast carcinomas, from women undergone surgery for primary invasive breast carcinoma between 1995 and 2001, were selected on the basis of negative staining for ER, PgR and HER2/neu (“BRCA-like”). In these patients, Methylation Specific-PCR and Bisulfite Sequencing on genomic DNA (obtained from sections of paraffin-embedded tissues and modified with sodium bisulfite) were used to assess the methylation pattern of BRCA1 promoter. BRCA1 immunohystochemical analysis (IHC) was performed in all patients. Results: We identified 17 patients with deleterious germline mutations in BRCA1. In “BRCA-like” patients, 13 methylated and 17 unmethylated cases were found by methylation analysis of BRCA1 promoter. The BRCA1 IHC was performed in all available samples ( table 1 ). Conclusions: Hypermethylation of BRCA1 promoter was found in 43% of “BRCA- like” patients. Expression of BRCA1 seems to correlate with hypermethylation of its promoter. Further studies are in progress to better understand the possible role of BRCA1 promoter hypermethylation in sporadic breast cancers. [Table: see text] No significant financial relationships to disclose.

scholarly journals BRCA1 Gene Expression in Breast Cancer: A Correlative Study between Real-time RT-PCR and Immunohistochemistry

2005 ◽  
Vol 53 (5) ◽  
pp. 621-629 ◽  
Author(s):  
Fahd Al-Mulla ◽  
Mahera Abdulrahman ◽  
Govindarajulu Varadharaj ◽  
Nadeem Akhter ◽  
Jehoram T. Anim
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Protein Expression ◽  
Real Time ◽  
Brca1 Gene ◽  
Mrna Levels ◽  
Rt Pcr ◽  
Brca1 Protein ◽  
Brca1 Mrna ◽  
Cancer Tissues

Breast cancer is a major cause of cancer-related mortality in women. There are major discrepancies concerning the usefulness of various antibodies in detecting breast cancer susceptibility gene 1 (BRCA1) protein and its subcellular localization. The aim of the present study was to determine the specificity and sensitivity of immunohistochemistry (IHC) as a screening method for demonstrating BRCA1 expression. BRCA1 gene expression in archival paraffin-embedded breast cancer tissues was studied simultaneously at the protein and mRNA levels, and the two findings were compared. Forty-eight archival paraffin-embedded breast cancer tissues were studied for BRCA1 gene expression at protein level by IHC using four different antibodies against different BRCA1 epitopes and at mRNA level using real-time RT-PCR. BRCA1 mRNA expression was reduced or absent in 79% of the samples, and this finding correlated significantly with loss of BRCA1 protein expression in 83% of breast cancer tissues using one BRCA1 antibody studied (AB-1, against N-terminus epitope). The specificity of this antibody was 91.3%, and its sensitivity was 66.6%. There was no significant correlation between BRCA1 mRNA and protein expression as demonstrated by the remaining three antibodies. Antibody 8F7 had the highest sensitivity of 100%, but its specificity was 30.4% if mRNA levels were considered as the reference standard.

scholarly journals Multi-view feature selection for identifying gene markers: a diversified biological data driven approach

2020 ◽  
Vol 21 (S18) ◽  
Author(s):  
Sudipta Acharya ◽  
Laizhong Cui ◽  
Yi Pan
Keyword(s):  
Gene Expression ◽  
Feature Selection ◽  
Gene Selection ◽  
Marker Gene ◽  
Biological Data ◽  
Protein Interaction Data ◽  
Marker Genes ◽  
Data Sets ◽  
Gene Markers ◽  
Multi Objective

Abstract Background In recent years, to investigate challenging bioinformatics problems, the utilization of multiple genomic and proteomic sources has become immensely popular among researchers. One such issue is feature or gene selection and identifying relevant and non-redundant marker genes from high dimensional gene expression data sets. In that context, designing an efficient feature selection algorithm exploiting knowledge from multiple potential biological resources may be an effective way to understand the spectrum of cancer or other diseases with applications in specific epidemiology for a particular population. Results In the current article, we design the feature selection and marker gene detection as a multi-view multi-objective clustering problem. Regarding that, we propose an Unsupervised Multi-View Multi-Objective clustering-based gene selection approach called UMVMO-select. Three important resources of biological data (gene ontology, protein interaction data, protein sequence) along with gene expression values are collectively utilized to design two different views. UMVMO-select aims to reduce gene space without/minimally compromising the sample classification efficiency and determines relevant and non-redundant gene markers from three cancer gene expression benchmark data sets. Conclusion A thorough comparative analysis has been performed with five clustering and nine existing feature selection methods with respect to several internal and external validity metrics. Obtained results reveal the supremacy of the proposed method. Reported results are also validated through a proper biological significance test and heatmap plotting.

scholarly journals Early and late stage MPN patients show distinct gene expression profiles in CD34+ cells

2021 ◽  
Author(s):  
Julian Baumeister ◽  
Tiago Maié ◽  
Nicolas Chatain ◽  
Lin Gan ◽  
Barbora Weinbergerova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Late Stage ◽  
Rna Splicing ◽  
Bone Marrow Cells ◽  
Myeloproliferative Neoplasms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Primary Myelofibrosis ◽  
Estrogen Signaling ◽  
Therapeutic Modalities

AbstractMyeloproliferative neoplasms (MPN), comprising essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are hematological disorders of the myeloid lineage characterized by hyperproliferation of mature blood cells. The prediction of the clinical course and progression remains difficult and new therapeutic modalities are required. We conducted a CD34+ gene expression study to identify signatures and potential biomarkers in the different MPN subtypes with the aim to improve treatment and prevent the transformation from the rather benign chronic state to a more malignant aggressive state. We report here on a systematic gene expression analysis (GEA) of CD34+ peripheral blood or bone marrow cells derived from 30 patients with MPN including all subtypes (ET (n = 6), PV (n = 11), PMF (n = 9), secondary MF (SMF; post-ET-/post-PV-MF; n = 4)) and six healthy donors. GEA revealed a variety of differentially regulated genes in the different MPN subtypes vs. controls, with a higher number in PMF/SMF (200/272 genes) than in ET/PV (132/121). PROGENγ analysis revealed significant induction of TNFα/NF-κB signaling (particularly in SMF) and reduction of estrogen signaling (PMF and SMF). Consistently, inflammatory GO terms were enriched in PMF/SMF, whereas RNA splicing–associated biological processes were downregulated in PMF. Differentially regulated genes that might be utilized as diagnostic/prognostic markers were identified, such as AREG, CYBB, DNTT, TIMD4, VCAM1, and S100 family members (S100A4/8/9/10/12). Additionally, 98 genes (including CLEC1B, CMTM5, CXCL8, DACH1, and RADX) were deregulated solely in SMF and may be used to predict progression from early to late stage MPN. Graphical abstract

scholarly journals 10P The clinical actionability of PTEN protein and gene expression analysis in HR- and HER2+ breast cancers

2021 ◽  
Vol 32 ◽  
pp. S25
Author(s):  
N. Fusco ◽  
E. Sajjadi ◽  
K. Venetis ◽  
M. Invernizzi ◽  
D. Gambini ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Breast Cancers ◽  
Pten Protein

scholarly journals Elevation of gene expression of Btg2, Gadd 153, and antioxidant markers in RONS-induced PC12 cells

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Aravind P ◽  
Sarojini R. Bulbule ◽  
Hemalatha N ◽  
Anushree G ◽  
Babu R.L ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endoplasmic Reticulum ◽  
Protein Expression ◽  
Pc12 Cells ◽  
Expression Pattern ◽  
High Glucose ◽  
Nitrosative Stress ◽  
Gene Expression Pattern ◽  
Marker Genes ◽  
Differential Stress

Abstract Background Free radicals generated in the biological system bring about modifications in biological molecules causing damage to their structure and function. Identifying the damage caused by ROS and RNS is important to predict the pathway of apoptosis due to stress in PC12 cells. The first defense mechanisms against them are antioxidants which act in various pathways through important cellular organelles like the mitochondria and endoplasmic reticulum. Specific biomarkers like Gadd153 which is a marker for endoplasmic reticulum stress, Nrf2 which responds to the redox changes and translocates the antioxidant response elements, and Btg2 which is an antioxidant regulator have not been addressed in different stress conditions previously in PC12 cells. Therefore, the study was conducted to analyze the gene expression pattern (SOD, Catalase, Btg2, Gadd153, and Nrf2) and the protein expression pattern (iNOS and MnSOD) of the antioxidant stress markers in differential stress-induced PC12 cells. Peroxynitrite (1 μM), rotenone (1 μM), H2O2(100 mM), and high glucose (33 mM) were used to induce oxidative and nitrosative stress in PC12 cells. Results The results obtained suggested that rotenone-induced PC12 cells showed a significant increase in the expression of catalase, Btg2, and Gadd153 compared to the control. Peroxynitrite-induced PC12 cells showed higher expression of Btg2 compared to the control. H2O2 and high glucose showed lesser expression compared to the control in all stress marker genes. In contrast, the Nrf2 gene expression is downregulated in all the stress-induced PC12 cells compared to the control. Further, MnSOD and iNOS protein expression studies suggest that PC12 cells exhibit a selective downregulation. Lower protein expression of MnSOD and iNOS may be resulted due to the mitochondrial dysfunction in peroxynitrite-, high glucose-, and H2O2-treated cells, whereas rotenone-induced cells showed lower expression, which could be the result of a dysfunction of the endoplasmic reticulum. Conclusion Different stress inducers like rotenone, peroxynitrite, H2O2, and high glucose increase the NO and ROS. Btg2 and Gadd153 genes were upregulated in the stress-induced cells, whereas the Nrf2 was significantly downregulated in differential stress-induced PC12 cells. Further, antioxidant marker genes were differentially expressed with different stress inducers.

scholarly journals Connectivity Map-based discovery of parbendazole reveals targetable human osteogenic pathway

2015 ◽  
Vol 112 (41) ◽  
pp. 12711-12716 ◽  
Author(s):  
Andrea M. Brum ◽  
Jeroen van de Peppel ◽  
Cindy S. van der Leije ◽  
Marijke Schreuders-Koedam ◽  
Marco Eijken ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alkaline Phosphatase ◽  
Osteoblast Differentiation ◽  
Target Genes ◽  
Focal Adhesions ◽  
Bone Fragility ◽  
Bone Morphogenetic Protein 2 ◽  
Marker Genes ◽  
Connectivity Map ◽  
Morphogenetic Protein

Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. In this study, we have identified pathways that stimulate differentiation of bone forming osteoblasts from human mesenchymal stromal cells (hMSCs). Gene expression profiling was performed in hMSCs differentiated toward osteoblasts (at 6 h). Significantly regulated genes were analyzed in silico, and the Connectivity Map (CMap) was used to identify candidate bone stimulatory compounds. The signature of parbendazole matches the expression changes observed for osteogenic hMSCs. Parbendazole stimulates osteoblast differentiation as indicated by increased alkaline phosphatase activity, mineralization, and up-regulation of bone marker genes (alkaline phosphatase/ALPL, osteopontin/SPP1, and bone sialoprotein II/IBSP) in a subset of the hMSC population resistant to the apoptotic effects of parbendazole. These osteogenic effects are independent of glucocorticoids because parbendazole does not up-regulate glucocorticoid receptor (GR) target genes and is not inhibited by the GR antagonist mifepristone. Parbendazole causes profound cytoskeletal changes including degradation of microtubules and increased focal adhesions. Stabilization of microtubules by pretreatment with Taxol inhibits osteoblast differentiation. Parbendazole up-regulates bone morphogenetic protein 2 (BMP-2) gene expression and activity. Cotreatment with the BMP-2 antagonist DMH1 limits, but does not block, parbendazole-induced mineralization. Using the CMap we have identified a previously unidentified lineage-specific, bone anabolic compound, parbendazole, which induces osteogenic differentiation through a combination of cytoskeletal changes and increased BMP-2 activity.

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