Simultaneous CXCL12 and ESR1 CpG island hypermethylation correlates with poor prognosis in sporadic breast cancer

Background CXCL12 is a chemokine that is constitutively expressed in many organs and tissues. CXCL12 promoter hypermethylation has been detected in primary breast tumours and contributes to their metastatic potential. It has been shown that the oestrogen receptor α ( ESR1 ) gene can also be silenced...

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Veröffentlicht in:BMC cancer Jg. 10; H. 1; S. 23
Hauptverfasser: Ramos, Edneia AS, Camargo, Anamaria A, Braun, Karin, Slowik, Renata, Cavalli, Iglenir J, Ribeiro, Enilze MSF, Pedrosa, Fábio de O, de Souza, Emanuel M, Costa, Fabrício F, Klassen, Giseli
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London BioMed Central 28.01.2010
BioMed Central Ltd
BMC
Schlagworte:
Adult
Aged
Aged, 80 and over
Biomedical and Life Sciences
Biomedicine
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer Research
Cell Line, Tumor
Chemokine CXCL12 - biosynthesis
Chemokine CXCL12 - genetics
Chemokines
CpG Islands
Development and progression
DNA Methylation
DNA Mutational Analysis
Estrogen
Estrogen Receptor alpha - biosynthesis
Estrogen Receptor alpha - genetics
Female
Gene Silencing
Genetic aspects
Genetic Predisposition to Disease
Health Promotion and Disease Prevention
Humans
Immunohistochemistry
Medicine/Public Health
Methylation
Middle Aged
Oncology
Physiological aspects
Prognosis
Promoter Regions, Genetic
Receptors
Research Article
Reverse Transcriptase Polymerase Chain Reaction
Risk factors
Surgical Oncology
United States
CXCL12 Expression
Breast Tumour Cell Line
ESR1 Gene
Primary Breast Tumour
Normal Cell Line
ISSN:1471-2407, 1471-2407
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Zusammenfassung:Background CXCL12 is a chemokine that is constitutively expressed in many organs and tissues. CXCL12 promoter hypermethylation has been detected in primary breast tumours and contributes to their metastatic potential. It has been shown that the oestrogen receptor α ( ESR1 ) gene can also be silenced by DNA methylation. In this study, we used methylation-specific PCR (MSP) to analyse the methylation status in two regions of the CXCL12 promoter and ESR1 in tumour cell lines and in primary breast tumour samples, and correlated our results with clinicopathological data. Methods First, we analysed CXCL12 expression in breast tumour cell lines by RT-PCR. We also used 5-aza-2'-deoxycytidine (5-aza-CdR) treatment and DNA bisulphite sequencing to study the promoter methylation for a specific region of CXCL12 in breast tumour cell lines. We evaluated CXCL12 and ESR1 methylation in primary tumour samples by methylation-specific PCR (MSP). Finally, promoter hypermethylation of these genes was analysed using Fisher's exact test and correlated with clinicopathological data using the Chi square test, Kaplan-Meier survival analysis and Cox regression analysis. Results CXCL12 promoter hypermethylation in the first region (island 2) and second region (island 4) was correlated with lack of expression of the gene in tumour cell lines. In the primary tumours, island 2 was hypermethylated in 14.5% of the samples and island 4 was hypermethylated in 54% of the samples. The ESR1 promoter was hypermethylated in 41% of breast tumour samples. In addition, the levels of ERα protein expression diminished with increased frequency of ESR1 methylation (p < 0.0001). This study also demonstrated that CXCL12 island 4 and ESR1 methylation occur simultaneously at a high frequency (p = 0.0220). Conclusions This is the first study showing a simultaneous involvement of epigenetic regulation for both CXCL12 and ESR1 genes in Brazilian women. The methylation status of both genes was significantly correlated with histologically advanced disease, the presence of metastases and death. Therefore, the methylation pattern of these genes could be used as a molecular marker for the prediction of breast cancer outcome.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1471-2407
1471-2407
DOI:10.1186/1471-2407-10-23