scholarly journals Identification of Gene Expression Signature in Estrogen Receptor Positive Breast Carcinoma

2010 ◽  
Vol 2 ◽  
pp. BIC.S3793 ◽  
Author(s):  
Arvind D. Thakkar ◽  
Hemanth Raj ◽  
Debarshi Chakrabarti ◽  
Ravishankar ◽  
N. Saravanan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Molecular Basis ◽  
Clinical Specimen ◽  
Gene Expression Signature ◽  
Breast Tumors ◽  
Significant Group ◽  
Six Genes

A significant group of patient with estrogen receptor (ER) α positive breast tumors fails to appreciably respond to endocrine therapy. An increased understanding of the molecular basis of estrogen-mediated signal transduction and resultant gene expression may lead to novel strategies for treating breast cancer. In this study, we sought to identify the dysregulated genes in breast tumors related to ERα status. Microarray analyses of 31 tumor samples showed 108 genes differentially expressed in ERα (+) and ERα (–) primary breast tumors. Further analyses of gene lists indicated that a significant number of dysregulated genes were involved in mRNA transcription and cellular differentiation. The majority of these genes were found to have promoter-binding sites for E74-like factor 5 (ELF5; 54.6% genes), E2F transcription factor 1 (E2F1; 22.2% genes), and nuclear transcription factor Y alpha (NFYA; 32.4% genes). Six candidate genes ( NTN4, SLC7A8, MLPH, ENPP1, LAMB2, and PLAT) with differential expression were selected for further validation studies using RT-qPCR (76 clinical specimen) and immunohistochemistry (48 clinical specimen). Our studies indicate significant overexpression of all the six genes in ERα (+) breast tumors as compared to ERα (–) breast tumors. In vitro studies using T-47D breast cancer cell line confirmed the estrogen dependant expression of four of the above six genes ( SLC7A8, ENPP1, LAMB2, and PLAT). Collectively, our study provides further insights into the molecular basis of estrogen-dependent breast cancer and identifies “candidate biomarkers” that could be useful for predicting endocrine responsiveness.

FOXA1 in breast cancer

2009 ◽  
Vol 11 ◽  
Author(s):  
Harikrishna Nakshatri ◽  
Sunil Badve
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Transcription Factor ◽  
Expression Patterns ◽  
Gene Expression Pattern ◽  
Gene Expression Signature ◽  
Specific Gene ◽  
Breast Cancers ◽  
Transcription Factor Network ◽  
Histopathological Classification

Breast cancer is a heterogeneous disease and classification is important for clinical management. At least five subtypes can be identified based on unique gene expression patterns; this subtype classification is distinct from the histopathological classification. The transcription factor network(s) required for the specific gene expression signature in each of these subtypes is currently being elucidated. The transcription factor network composed of the oestrogen (estrogen) receptor α (ERα), FOXA1 and GATA3 may control the gene expression pattern in luminal subtype A breast cancers. Breast cancers that are dependent on this network correspond to well-differentiated and hormone-therapy-responsive tumours with good prognosis. In this review, we discuss the interplay between these transcription factors with a particular emphasis on FOXA1 structure and function, and its ability to control ERα function. Additionally, we discuss modulators of FOXA1 function, ERα–FOXA1–GATA3 downstream targets, and potential therapeutic agents that may increase differentiation through FOXA1.

scholarly journals Region-specific glucocorticoid receptor promoter methylation has both positive and negative prognostic value in patients with estrogen receptor-positive breast cancer

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Hilary Snider ◽  
Brithica Villavarajan ◽  
Yingwei Peng ◽  
Lois E. Shepherd ◽  
Andrew C. Robinson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Glucocorticoid Receptor ◽  
Promoter Methylation ◽  
Prognostic Value ◽  
Breast Tumors ◽  
Tamoxifen Treatment ◽  
Promoter Regions ◽  
Estrogen Receptor Positive

Abstract Background The glucocorticoid receptor (NR3C1, GR) is frequently downregulated in breast tumors, and evidence suggests it acts as a tumor suppressor in estrogen receptor-positive (ER+) breast cancer. We previously found that methylation of the GR promoter CpG island represses gene expression and occurs in ER+ breast tumors. In this study, the prognostic and predictive value of GR methylation was examined in ER+ patients from the CCTG MA.12 clinical trial of tamoxifen versus placebo in women with early breast cancer. Methods We developed a targeted multiplex bisulfite next-generation sequencing assay to detect methylation at multiple GR promoter regions in DNA from formalin-fixed paraffin-embedded (FFPE) samples. Following validation in a small cohort of breast tumors, ER+ FFPE tumor samples from MA.12 (n = 208) were tested. Survival analyses evaluated the impact of GR promoter methylation on patient overall survival (OS) and disease-free survival (DFS). Results An analysis of TCGA data found that GR methylation is prevalent in ER+ tumors and is associated with decreased gene expression and analysis of public microarray data (KM Plotter) linked decreased GR expression to a poor outcome. In MA.12, two GR promoter regions (U and C) each had prognostic value, but with opposite effects on the outcome. U methylation was associated with poor OS (HR = 1.79, P = 0.041) whereas C methylation was associated with better OS (HR = 0.40, P = 0.040) and DFS (HR = 0.49, P = 0.037). The classification of patients based on the methylation status of the two regions was prognostic for OS (P = 0.006) and DFS (P = 0.041) and revealed a group of patients (U methylated, C unmethylated) with very poor outcomes. Placebo-treated patients in this high-risk group had worse OS (HR = 2.86, P = 0.002) and DFS (HR = 2.09, P = 0.014) compared to the rest of the cohort. Conclusion Region-specific GR promoter methylation was an independent prognostic marker for patient survival and identified a subset of patients with poor prognosis, particularly without tamoxifen treatment. These findings provide a foundation for future studies into GR methylation as a promising prognostic biomarker in ER+ breast cancer.

scholarly journals Gene expression signature of estrogen receptor α status in breast cancer

BMC Genomics ◽  
2005 ◽  
Vol 6 (1) ◽  
Author(s):  
Martín C Abba ◽  
Yuhui Hu ◽  
Hongxia Sun ◽  
Jeffrey A Drake ◽  
Sally Gaddis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Gene Expression Signature ◽  
Estrogen Receptor Α ◽  
Expression Signature

scholarly journals Estrogen receptor regulates insulin-like growth factor-I receptor gene expression in breast tumor cells: involvement of transcription factor Sp1

2006 ◽  
Vol 191 (3) ◽  
pp. 605-612 ◽  
Author(s):  
Sharon Maor ◽  
Doris Mayer ◽  
Ronit I Yarden ◽  
Adrian V Lee ◽  
Rive Sarfstein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Receptor Gene ◽  
Luciferase Reporter ◽  
Cancer Etiology ◽  
Estradiol Treatment ◽  
Igf I ◽  
Mcf 7

The insulin-like growth factors, IGF-I and IGF-II are a familyof mitogenic polypeptides with important roles in growth and differentiation. The biological actions of the IGFs are mediated by the IGF-I receptor (IGF-IR), a cell-surface tyrosine kinase, whose activation by serum IGF-I seems to be a key step in breast cancer initiation. Evidence accumulated indicates that estrogens stimulate the expression and activity of IGF axis components. The aim of our study was to examine the transcriptional mechanisms involved in regulation of IGF-IR gene expression by the estrogen receptor (ER). For this purpose, transient transfections using an IGF-IR promoter-luciferase reporter plasmid were performed in breast cancer-c derived ER-positive MCF-7 cells and isogenic ER-negative C4 cells. To examine the potential involvement of zinc-finger nuclear proteins in the transactivating effect of estrogens, chromatin immunoprecipitation (ChIP) experiments were performed using an Sp1 antibody, along with the Sp1-family-binding inhibitor Mithramycin A. The results obtained indicate that basal IGF-IR promoter activity was 5.8-fold higher in MCF-7 than in C4 cells. Estradiol treatment significantly activated the IGF-IR promoter in MCF-7, but not in C4 cells. Furthermore, the estrogen responsive region in the IGF-IR promoter was mapped to a GC-rich sequence located between nucleotides −40 and −188 in the 5′ flanking region. ChIP experiments revealed that at least part of the estrogen effect on IGF-IR expression was mediated through activation of the Sp1 transcription factor. In summary, our studies demonstrate that IGF-IR gene transcription in breast cancer cells is controlled by interactions between ERα and Sp1. Dysregulated expression of the IGF-IR gene may have pathologic consequences with relevance in breast cancer etiology.

scholarly journals TWIST1 Gene expression as a biomarker for predicting primary doxorubicin resistance in breast cancer

2019 ◽  
Vol 22 (2) ◽  
pp. 25-30
Author(s):  
S Demir ◽  
MH Müslümanoğlu ◽  
M Müslümanoğlu ◽  
S Başaran ◽  
ZZ Çalay ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Transcription Factor ◽  
Cancer Patients ◽  
Breast Tumors ◽  
Chemotherapeutic Agents ◽  
Primary Breast Tumor ◽  
Breast Cancer Patients ◽  
Significant Difference ◽  
Transcription Factor Expression

AbstractDoxorubicin is one of the most commonly used chemotherapeutic agents for adjuvant chemotherapy of breast cancer. In the studies focused on finding biomarkers to predict the response of the patients and tumors to the drugs used, the Twist transcription factor has been suggested as a candidate biomarker for predicting chemo-resistance of breast tumors. In this study, we aimed to investigate the relationship between TWIST transcription factor expression and the effectiveness of doxorubicin treatment on directly taken primary tumor samples from chemotherapy-naive breast cancer patients. Twenty-six primary breast tumor samples taken from 26 different breast cancer patients were included in this study. Adenosine triphosphate tumor chemo-sensitivity assay (ATP-TCA) has been used to determine tumor response to doxorubicin and real-time reverse-transcription polymerase chain reaction (RT-PCR) was used for analyzing the TWIST1 gene expression of tumors. There was a significant difference in TWIST gene expression between responder and non responder tumors (p <0.05). The TWIST gene expression of the drug-resistant group was higher than the responsive group. This difference was not dependent on the histopathological features of tumors. In conclusion, compatible with earlier studies that have been performed with cell lines, the current study supports the role of higher TWIST gene expression as a biomarker for predicting the response of breast tumors to chemo-therapeutic agent doxorubicin.

scholarly journals Epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer

2021 ◽  
Author(s):  
Jørgen Ankill ◽  
Miriam Ragle Aure ◽  
Sunniva Bjørklund ◽  
Severin Langberg ◽  
Vessela N. Kristensen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factor ◽  
Breast Tumors ◽  
Epigenetic Alterations ◽  
Factor Binding ◽  
Chromatin Loops ◽  
Cancer Pathogenesis ◽  
Genome Wide

Breast cancer is a highly heterogeneous disease driven by multiple factors including genetic and epigenetic alterations. DNA methylation patterns have been shown to be altered on a genome-wide scale and previous studies have highlighted the critical role of aberrant DNA methylation on gene expression and breast cancer pathogenesis. Here, we perform genome-wide expression-methylation Quantitative Trait Loci (emQTL), a method for integration of CpG methylation and gene expression to identify disease-driving genes under epigenetic control. By grouping these emQTLs by biclustering we identify associations representing important biological processes associated with breast cancer pathogenesis such as proliferation and tumor infiltrating fibroblasts. We report hypomethylation at enhancers carrying transcription factor binding sites of key proliferation-driving transcription factors such as CEBP-β, FOSL1, and FOSL2, with concomitant high expression of cell cycle- and proliferation-related genes in aggressive breast tumors. The identified CpGs and genes were found to be connected through chromatin loops, together indicating that proliferation in aggressive breast tumors is under epigenetic regulation by DNA methylation. Interestingly, there was a significant correlation between proliferation-related DNA methylation and gene expression also within subtypes of breast cancer, thereby showing that varying proliferation may be explained by epigenetic profiles across breast cancer subtypes. Indeed, the identified proliferation gene signature was prognostic both in the Luminal A and Luminal B subtypes. Taken together, we show that proliferation in breast cancer is linked to hypomethylation at specific enhancers and transcription factor binding mediated through chromatin loops.

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