THE TRANSCRIPTION FACTOR Y-BOX BINDING PROTEIN-1 (YB-1) INDUCES EXPRESSION OF THE PIK3CA ONCOGENE LEADING TO INCREASED INVASION OFBASAL-LIKE BREAST CARCINOMA CELLS

2008 ◽  
Vol 31 (4) ◽  
pp. 3
Author(s):  
Arezoo Astanehe ◽  
Melanie Finkbeiner ◽  
Karen To ◽  
Sandra E Dunn
Keyword(s):  
Breast Cancer ◽  
Breast Carcinoma ◽  
Chromatin Immunoprecipitation ◽  
Copy Number ◽  
Pik3ca Mutation ◽  
Comparative Genomic ◽  
Over Expression ◽  
Protein Levels ◽  
A Genome ◽  
On Chip

Background: Basal-like breast carcinoma (BLBC) is the mostaggressive subtype of breast cancer. 73% of BLBC over-express YB-1, anoncogenic transcription/translation factor. PIK3CA, which codes for the p110? catalytic subunit ofphosphatidylinositol-3-kinase (PI3K), is another oncogene. The PI3K signalling pathway is fundamental in the regulation of many cellular functions and isoften deregulated in cancer. Despite its importance, the knowledge on the transcriptional regulation of PIK3CA is limited. Indeed, we have recently published the first report on the PIK3CA promoter. Methods and Results: A genome-wide chromatin immunoprecipitation on chip (ChIP-on-chip) analysis of a BLBC cell-line(SUM149) suggested binding of YB-1 to the PIK3CA promoter. This binding was verified using traditional chromatin immunoprecipitation (ChIP). Furthermore, electrophoretic mobility shift assay (EMSA) using oligonucleotides with eitherwild-type or mutated YB-1 responsive elements mapped YB-1 binding to three sites on the PIK3CA promoter. Silencing YB-1 in BLBC cell-lines (SUM149, HCC1937, andMDA-MB-231) decreased, while over-expression of YB-1 increased the PIK3CA promoter activity, transcript, and protein levels. Interestingly, array comparative genomic hybridization(aCGH) and quantitative PCR demonstrated PIK3CA copy number gains in HCC1937 andMDA-MB-231 cells. Although PIK3CA amplifications are overall uncommon (9%) in breast cancer, we demonstrated here that low level gains in PIK3CA copy number are present in 30%of primary BLBC cases. Furthermore, it has previously been demonstrated that mutations of PIK3CA are the most common genetic aberration (27%) found in breast cancer. These mutations lead to constitutive activation of p110? and are highly oncogenic. Over-expression of YB-1in MCF-7 cells, which harbour an activating PIK3CA mutation, increased PIK3CA transcript and protein levels. Furthermore, induction of PIK3CA by YB-1 leads to increased levels of urokinase plasminogenactivator (uPA) and invasion. Conclusions: Our data demonstrates that YB-1 binds to the PIK3CA promoter and induces itsexpression whether the gene is wild-type or amplified. Moreover, since YB-1induces expression of the active mutant p110?, then therapeutic inhibition of YB-1 may lead to decreased p110? and interference with the constitutively activated PI3K pathway in cancers. In addition, the YB-1/PIK3CA/uPA network provides information regarding the possible therapeutic targets for prevention of breast cancer invasion and metastasis. A.A. is supported by a Child and Family–CIHR–UBC MD/PhD Studentship Award.

Somatic Activation of KIT in Distinct Subtypes of Melanoma

2006 ◽  
Vol 24 (26) ◽  
pp. 4340-4346 ◽  
Author(s):  
John A. Curtin ◽  
Klaus Busam ◽  
Daniel Pinkel ◽  
Boris C. Bastian
Keyword(s):  
Map Kinase ◽  
Copy Number ◽  
Significant Proportion ◽  
Therapeutic Benefit ◽  
Comparative Genomic ◽  
Protein Levels ◽  
Hybridization Data ◽  
Exposed Skin ◽  
Mitogen Activated Protein ◽  
Melanoma Subtypes

Purpose Melanomas on mucosal membranes, acral skin (soles, palms, and nail bed), and skin with chronic sun-induced damage have infrequent mutations in BRAF and NRAS, genes within the mitogen-activated protein (MAP) kinase pathway commonly mutated in melanomas on intermittently sun-exposed skin. This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the melanoma types with infrequent mutations of BRAF and NRAS. Patients and Methods We analyzed array comparative genomic hybridization data from 102 primary melanomas (38 from mucosa, 28 from acral skin, and 18 from skin with and 18 from skin without chronic sun-induced damage) for DNA copy number aberrations specific to melanoma subtypes where mutations in BRAF and NRAS are infrequent. A narrow amplification on 4q12 was found, and candidate genes within it were analyzed. Results Oncogenic mutations in KIT were found in three of seven tumors with amplifications. Examination of all 102 primary melanomas found mutations and/or copy number increases of KIT in 39% of mucosal, 36% of acral, and 28% of melanomas on chronically sun-damaged skin, but not in any (0%) melanomas on skin without chronic sun damage. Seventy-nine percent of tumors with mutations and 53% of tumors with multiple copies of KIT demonstrated increased KIT protein levels. Conclusion KIT is an important oncogene in melanoma. Because the majority of the KIT mutations we found in melanoma also occur in imatinib-responsive cancers of other types, imatinib may offer an immediate therapeutic benefit for a significant proportion of the global melanoma burden.

scholarly journals A Genome-Wide Association Study to Identify Potential Germline Copy Number Variants for Sporadic Breast Cancer Susceptibility

2016 ◽  
Vol 149 (3) ◽  
pp. 156-164 ◽  
Author(s):  
Yadav Sapkota ◽  
Ashok Narasimhan ◽  
Mahalakshmi Kumaran ◽  
Badan S. Sehrawat ◽  
Sambasivarao Damaraju
Keyword(s):  
Breast Cancer ◽  
Association Study ◽  
Copy Number ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Frequency Effect ◽  
Potential Candidate ◽  
Disease Etiology ◽  
Genome Wide ◽  
A Genome

Breast cancer (BC) predisposition in populations arises from both genetic and nongenetic risk factors. Structural variations such as copy number variations (CNVs) are heritable determinants for disease susceptibility. The primary objectives of this study are (1) to identify CNVs associated with sporadic BC using a genome-wide association study (GWAS) design; (2) to utilize 2 distinct CNV calling algorithms to identify concordant CNVs as a strategy to reduce false positive associations in the hypothesis-generating GWAS discovery phase, and (3) to identify potential candidate CNVs for follow-up replication studies. We used Affymetrix SNP Array 6.0 data profiled on Caucasian subjects (422 cases/348 controls) to call CNVs using algorithms implemented in Nexus Copy Number and Partek Genomics Suite software. Nexus algorithm identified CNVs associated with BC (731 autosomal CNVs with >5% frequency in the total sample and Q < 0.05). Thirteen CNVs were identified when Partek algorithm-called CNVs were overlapped with Nexus-identified CNVs; these CNVs showed concordances for frequency, effect size, and direction. Coding genes present within BC-associated CNVs were known to play a role in disease etiology and prognosis. Long noncoding RNAs identified within CNVs showed tissue-specific expression, indicating potential functional relevance of the findings. The identified candidate CNVs warrant independent replication.

scholarly journals The first decade of estrogen receptor cistromics in breast cancer

2016 ◽  
Vol 229 (2) ◽  
pp. R43-R56 ◽  
Author(s):  
Koen D Flach ◽  
Wilbert Zwart
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Tiling Array ◽  
Estrogen Receptor Α ◽  
Sequencing Technologies ◽  
Hormone Receptor Positive ◽  
Genome Wide ◽  
A Genome ◽  
On Chip

The advent of genome-wide transcription factor profiling has revolutionized the field of breast cancer research. Estrogen receptor α (ERα), the major drug target in hormone receptor-positive breast cancer, has been known as a key transcriptional regulator in tumor progression for over 30 years. Even though this function of ERα is heavily exploited and widely accepted as an Achilles heel for hormonal breast cancer, only since the last decade we have been able to understand how this transcription factor is functioning on a genome-wide scale. Initial ChIP-on-chip (chromatin immunoprecipitation coupled with tiling array) analyses have taught us that ERα is an enhancer-associated factor binding to many thousands of sites throughout the human genome and revealed the identity of a number of directly interacting transcription factors that are essential for ERα action. More recently, with the development of massive parallel sequencing technologies and refinements thereof in sample processing, a genome-wide interrogation of ERα has become feasible and affordable with unprecedented data quality and richness. These studies have revealed numerous additional biological insights into ERα behavior in cell lines and especially in clinical specimens. Therefore, what have we actually learned during this first decade of cistromics in breast cancer and where may future developments in the field take us?

scholarly journals GeneBreak: detection of recurrent DNA copy number aberration-associated chromosomal breakpoints within genes

F1000Research ◽  
2017 ◽  
Vol 5 ◽  
pp. 2340
Author(s):  
Evert van den Broek ◽  
Stef van Lieshout ◽  
Christian Rausch ◽  
Bauke Ylstra ◽  
Mark A. van de Wiel ◽  
...  
Keyword(s):  
Computational Methods ◽  
Chromosomal Aberrations ◽  
Copy Number ◽  
Comparative Genomic ◽  
Multiple Testing Correction ◽  
Dna Copy Number ◽  
Link Type ◽  
Genomic Location ◽  
A Genome ◽  
Chromosomal Breakpoints

Development of cancer is driven by somatic alterations, including numerical and structural chromosomal aberrations. Currently, several computational methods are available and are widely applied to detect numerical copy number aberrations (CNAs) of chromosomal segments in tumor genomes. However, there is lack of computational methods that systematically detect structural chromosomal aberrations by virtue of the genomic location of CNA-associated chromosomal breaks and identify genes that appear non-randomly affected by chromosomal breakpoints across (large) series of tumor samples. ‘GeneBreak’ is developed to systematically identify genes recurrently affected by the genomic location of chromosomal CNA-associated breaks by a genome-wide approach, which can be applied to DNA copy number data obtained by array-Comparative Genomic Hybridization (CGH) or by (low-pass) whole genome sequencing (WGS). First, ‘GeneBreak’ collects the genomic locations of chromosomal CNA-associated breaks that were previously pinpointed by the segmentation algorithm that was applied to obtain CNA profiles. Next, a tailored annotation approach for breakpoint-to-gene mapping is implemented. Finally, dedicated cohort-based statistics is incorporated with correction for covariates that influence the probability to be a breakpoint gene. In addition, multiple testing correction is integrated to reveal recurrent breakpoint events. This easy-to-use algorithm, ‘GeneBreak’, is implemented in R (www.cran.r-project.org) and is available from Bioconductor (www.bioconductor.org/packages/release/bioc/html/GeneBreak.html).

scholarly journals Lytic Viral Replication as a Contributor to theDetection of Epstein-Barr Virus in BreastCancer

2003 ◽  
Vol 77 (24) ◽  
pp. 13267-13274 ◽  
Author(s):  
J. Huang ◽  
H. Chen ◽  
L. Hutt-Fletcher ◽  
R. F. Ambinder ◽  
S. D. Hayward
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Breast Carcinoma ◽  
Reverse Transcription ◽  
Copy Number ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Ebv Infection ◽  
Reverse Transcription Pcr ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) has an accepted association with the epithelial malignancy nasopharyngeal carcinoma and has also been reported in other more controversial carcinoma settings. Evaluation of EBV association with epithelial carcinomas such as breast cancer would benefit from a better understanding of the outcome of EBV infection of these cells. Cell-free preparations of a green fluorescent protein-expressing virus, BX1, were used to infect breast cancer cell lines, which were then examined for EBV gene expression and viral genome copy number. Reverse transcription-PCR analyses revealed that the cells supported a mixture of latency II and lytic EBV gene expression. Lytic Zta and BMRF1 protein expression was detected by immunohistochemistry, and DNA PCR analyses estimated an EBV copy number of 300 to 600 genomes per infected cell. Evidence for lytic EBV expression was also found in breast tissue, where reverse transcription-PCR analyses detected lytic Zta transcripts in 7 of 10 breast carcinoma tissues and 4 of 10 normal tissues from the same patients. Scattered cells immunoreactive for Zta protein were also detectable in breast carcinoma. Quantitative real-time PCR analysis of EBV-positive breast carcinoma tissues suggested that less than 0.1% of the cells contained viral genomes. We suggest that sporadic lytic EBV infection may contribute to PCR-based detection of EBV in traditionally nonvirally associated epithelial malignancies.

scholarly journals Nexus Between Genome-Wide Copy Number Variations and Autism Spectrum Disorder in Northeast Han Chinese Population

2021 ◽  
Author(s):  
Shuang Qiu ◽  
Xianling Cong ◽  
Yan Li ◽  
Jikang Shi ◽  
Yingjia Qiu ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Copy Number ◽  
Chinese Population ◽  
Autism Spectrum ◽  
Han Chinese ◽  
Spectrum Disorder ◽  
Comparative Genomic ◽  
Han Chinese Population ◽  
Genome Wide ◽  
A Genome

Abstract Background: Autism spectrum disorder (ASD) is a common neurodevelopmental condition, with an increasing prevalence worldwide. Copy number variation (CNV), as one of genetic factors, is involved in ASD etiology. However, there exist substantial differences in terms of location and frequency of some CNVs in the general Asian population. Whole-genome studies of CNVs in Northeast Han Chinese samples are still lacking, necessitating our ongoing work to investigate the characteristics of CNVs in a Northeast Han Chinese population with clinically diagnosed ASD.Methods: We performed a genome-wide CNVs screening in Northeast Han Chinese individuals with ASD using array-based comparative genomic hybridization.Results: We found 22 kinds of CNVs (six deletions and 16 duplications) were potential pathogenic. These CNVs were distributed in chromosome 1p36.33, 1p36.31, 1q42.13, 2p23.1-p22.3, 5p15.33, 5p15.33-p15.2, 7p22.3, 7p22.3-p22.2, 7q22.1-q22.2, 10q23.2-q23.31, 10q26.2-q26.3, 11p15.5, 11q25, 12p12.1-p11.23, 14q11.2, 15q13.3, 16p13.3, 16q21, 22q13.31-q13.33, and Xq12-q13.1. Additionally, we found 20 potential pathogenic genes of ASD in our population, including eight protein coding genes (six duplications [DRD4, HRAS, OPHN1, SHANK3, SLC6A3, and TSC2] and two deletions [CHRNA7 and PTEN]) and 12 microRNAs genes (ten duplications [MIR202, MIR210, MIR3178, MIR339, MIR4516, MIR4717, MIR483, MIR675, MIR6821, and MIR940] and two deletions [MIR107 and MIR558]).Limitations: The sample size in our study may confer limited statistical power to discover significant findings. De novo or inherited of the CNVs were not be classified because of the lack of data from parents.Conclusions: We identified CNVs and genes implicated in ASD risks, conferring perception to further reveal ASD etiology.

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