Functional variants at the 21q22.3 locus involved in breast cancer progression identified by screening of genome-wide estrogen response elements View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-10-09

AUTHORS

Chia-Ni Hsiung, Hou-Wei Chu, Yuan-Ling Huang, Wen-Cheng Chou, Ling-Yueh Hu, Huan-Ming Hsu, Pei-Ei Wu, Ming-Feng Hou, Jyh-Cherng Yu, Chen-Yang Shen

ABSTRACT

INTRODUCTION: Estrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the regulatory region of estrogen-responsive genes and regulates their transcription. Sequence variants in the regulatory regions have the potential to affect the transcription factor-regulatory sequence interaction, resulting in altered expression of target genes. This study explored the association between single-nucleotide polymorphisms (SNPs) within the ERE-associated sequences and breast cancer progression. METHODS: The ERE-associated sequences throughout the whole genome that have been demonstrated to bind ERα in vivo were blasted against online information from SNP data sets and 54 SNPs located adjacent to estrogen-responsive genes were selected for genotyping in two independent cohorts of breast cancer patients: 779 patients in the initial screening stage and another 888 in the validation stage. Deaths due to breast cancer or recurrence of breast cancer were defined as the respective events of interest, and the hazard ratios of individual SNPs were estimated based on the Cox proportional hazards model. Furthermore, functional assays were performed, and information from publicly available genomic data and bioinformatics platforms were used to provide additional evidence for the associations identified in the association analyses. RESULTS: The SNPs at 21q22.3 ERE were significantly associated with overall survival and disease-free survival of patients. Furthermore, these 21q22.3 SNPs (rs2839494 and rs1078272) could affect the binding of this ERE-associated sequence to ERα or Rad21 (an ERα coactivator), respectively, which resulted in a difference in ERα-activated expression of the reporter gene. CONCLUSION: These findings support the idea that functional variants in the ERα-regulating sequence at 21q22.3 are important in determining breast cancer progression. More... »

PAGES

455

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s13058-014-0455-1

DOI

http://dx.doi.org/10.1186/s13058-014-0455-1

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https://app.dimensions.ai/details/publication/pub.1009219452

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25298020


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32 schema:description INTRODUCTION: Estrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the regulatory region of estrogen-responsive genes and regulates their transcription. Sequence variants in the regulatory regions have the potential to affect the transcription factor-regulatory sequence interaction, resulting in altered expression of target genes. This study explored the association between single-nucleotide polymorphisms (SNPs) within the ERE-associated sequences and breast cancer progression. METHODS: The ERE-associated sequences throughout the whole genome that have been demonstrated to bind ERα in vivo were blasted against online information from SNP data sets and 54 SNPs located adjacent to estrogen-responsive genes were selected for genotyping in two independent cohorts of breast cancer patients: 779 patients in the initial screening stage and another 888 in the validation stage. Deaths due to breast cancer or recurrence of breast cancer were defined as the respective events of interest, and the hazard ratios of individual SNPs were estimated based on the Cox proportional hazards model. Furthermore, functional assays were performed, and information from publicly available genomic data and bioinformatics platforms were used to provide additional evidence for the associations identified in the association analyses. RESULTS: The SNPs at 21q22.3 ERE were significantly associated with overall survival and disease-free survival of patients. Furthermore, these 21q22.3 SNPs (rs2839494 and rs1078272) could affect the binding of this ERE-associated sequence to ERα or Rad21 (an ERα coactivator), respectively, which resulted in a difference in ERα-activated expression of the reporter gene. CONCLUSION: These findings support the idea that functional variants in the ERα-regulating sequence at 21q22.3 are important in determining breast cancer progression.
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39 schema:keywords Cox proportional hazards model
40 ERα
41 ERα-activated expression
42 ERα-regulating sequence
43 RAD21
44 SNP data sets
45 additional evidence
46 altered expression
47 analysis
48 assays
49 association
50 association analysis
51 available genomic data
52 binding
53 bioinformatics platform
54 breast cancer
55 breast cancer patients
56 breast cancer progression
57 cancer
58 cancer patients
59 cancer progression
60 cohort
61 complexes
62 data
63 data sets
64 death
65 differences
66 disease-free survival
67 elements
68 estrogen
69 estrogen receptor
70 estrogen response element
71 estrogen-responsive genes
72 events
73 evidence
74 expression
75 factor-regulatory sequence interaction
76 findings
77 functional assays
78 functional variants
79 genes
80 genome
81 genome-wide estrogen response elements
82 genomic data
83 hazard ratio
84 hazards model
85 idea
86 independent cohort
87 individual single nucleotide polymorphisms
88 information
89 initial screening stage
90 interaction
91 interest
92 loci
93 model
94 online information
95 overall survival
96 patients
97 platform
98 polymorphism
99 potential
100 progression
101 proportional hazards model
102 ratio
103 receptors
104 recurrence
105 region
106 regulatory region
107 reporter gene
108 respective events
109 response element
110 screening stage
111 sequence
112 sequence interactions
113 set
114 single nucleotide polymorphisms
115 stage
116 study
117 survival
118 target genes
119 transcription
120 transcription factor-regulatory sequence interaction
121 validation stage
122 variants
123 vivo
124 whole genome
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