Methylation status of estrogen receptor α (ESR1) gene promoters in human cancer cell lines
Date Issued
2006
Date
2006
Author(s)
Chien, Shu-Chin
DOI
zh-TW
Abstract
It is well-known that estrogens play an important role in sexual development, reproduction and pathological processes in gynecologic tissues such as the mammary and uterine carcinomas. Estrogens exert these changes through the superfamily of nuclear hormone receptors which act as ligand-activated transcriptional factors. Currently two ER receptors (αandβ) coded on different genes (ESR1 and ESR2 genes respectively) have been identified. Comparing to ERβ, ERα is expressed in a great variety of human tissues. Its expression level varies considerably among different cell types and tissues due to the specific stimulation or repression by estrogens in a tissue-dependent manner. The possibility for the tissue-specific effects of estrogens may be from the differential and spatio-temporal expression of ERα. To understand the molecular mechanisms that control the tissue specific pattern of ERα could be valuable in identifying the various effects of estrogens on different biological processes.
The human ESR1 cDNA was cloned in 1986 and the gene consists of 8 coding exons spanning 140 kb of chromosome 6q25.1 locus. Until now, there have been very few reports about mutations of coding regions or other structural alterations of the ESR1 gene in various cancers. One possible mechanism for inactivating the transcriptional status is methylation of CpG islands in ESR1 gene due to the large distances between promoters. Previous studies on the structure and organization of the human ESR1 gene indicated that its transcriptional activity was probably controlled by up to six promoters. The differential expression of ERα protein in different tissues was demonstrated to be achieved by multiple promoter usage that aroused the possibility of responding to distinct combinations of factors present in different tissues. The discovery of six promoters at least in the ESR1 gene has led us to suggest that differential promoter usage through CGIs methylation pathway could be one mechanism regulating expression of the estrogen receptor α in various tissues.
In this study we comprehensively analyzed methylation status of six promoter regions in ESR1 gene in cancer cell lines and normal tissues by using bisulfite direct sequencing assay. Our results indicate that methylation status in six ESR1 promoters varies in different cancer cell lines. Currently ERαis a well-established prognostic marker in breast cancer, predicting the likelihood of a patient’s response to adjuvant endocrine therapy. The major finding of this work is that methylation status in ESR1 promoter A, B, C, D and F regions is dramatically different in ER(+) and ER(-) breast cancer cell lines. Selective promoter usage in genes containing multiple promoters such as ESR1 gene may be possible clinical application of promoter-specific methylation. Therefore, the different methylation profiles of ESR1 promoters in different cancer cell lines may provide a basis for further epigenetic analysis to distinguish different cancers.
To enrich the information obtained from bisulfite sequencing technique, we observed all or none methylated CpG sites within the amplified fragments in various cancer cell lines (0% or 100% methylation density, the percentage of methylated CpG sites within the amplified CpG sites). Smiraglia et al. reported that cancer cell lines exhibit a higher degree of methylation than normal tissues resulting from the end stage of carcinogenesis. In addition, it shows different methylation status in promoter A, B and F between cervical cancer cell lines and normal cervical tissues. However they may not truly represent each cancer in tissue and this result can be probably used for advanced analysis or as a molecular marker of cancer if we get the same result in primary cancer tissues. Further research in primary tumors is required in order to clarify the possible connection to cancer and quantification of methylation severity should also be emphasized due to the heterogeneous process of carcinogenesis.
Subjects
甲基化
methylation
SDGs
Type
text
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