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GSTP1 promoter haplotypes affect DNA methylation levels and promoter activity in breast carcinomas.
Cancer Res. 2008 Jul 15; 68(14):5562-71.CR

Abstract

The CpG island spanning the transcription start of the glutathione S-transferase P1 becomes methylated in a variety of human cancers including breast cancer. To study the effect of sequence variation on hypermethylation of the GSTP1 promoter, we analyzed the genetic and epigenetic variability in 90 tumors from patients with locally advanced breast cancer. High-resolution quantitative analysis revealed large variability in the DNA methylation levels. Lack of methylation was more often observed in the basal and normal-like estrogen receptor (ER)-negative tumors, and methylated GSTP1 was associated with better overall survival (P = 0.00063). Studies of the genetic variation identified 14 different haplotypes. The distribution of methylation levels of tumors homozygous for the most frequent haplotype was significantly different from other haplotype combinations (P = 0.011), the difference being more pronounced in ER-positive (P = 0.005) and progesterone receptor-positive (P = 0.008) tumors. Regression modeling identified the ER status and haplotype as the main determinants of DNA methylation variability. We identified a putative c-Myb response element (MRE) that was present in one of two minimal promoter haplotypes. In vitro analysis showed that c-Myb binds to the MRE, but binding was weakened by the two polymorphisms. Transient cotransfections in luminal-type and basal-like breast cancer cell lines confirmed cell-specific differential binding of c-Myb to the polymorphic sites, leading to a change in the expression from the GSTP1 promoter in vivo. GSTP1 expression was moderately but significantly (P = 0.01) reduced after siRNA-mediated knockdown of c-Myb. Our results indicate that haplotype structure of a promoter is important for the extent of DNA methylation.

Authors+Show Affiliations

Department of Genetics, The Norwegian Radium Hospital, Rikshospitalet University Hospital, Montebello, Oslo, Norway.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18632608

Citation

Rønneberg, Jo Anders, et al. "GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas." Cancer Research, vol. 68, no. 14, 2008, pp. 5562-71.
Rønneberg JA, Tost J, Solvang HK, et al. GSTP1 promoter haplotypes affect DNA methylation levels and promoter activity in breast carcinomas. Cancer Res. 2008;68(14):5562-71.
Rønneberg, J. A., Tost, J., Solvang, H. K., Alnaes, G. I., Johansen, F. E., Brendeford, E. M., Yakhini, Z., Gut, I. G., Lønning, P. E., Børresen-Dale, A. L., Gabrielsen, O. S., & Kristensen, V. N. (2008). GSTP1 promoter haplotypes affect DNA methylation levels and promoter activity in breast carcinomas. Cancer Research, 68(14), 5562-71. https://doi.org/10.1158/0008-5472.CAN-07-5828
Rønneberg JA, et al. GSTP1 Promoter Haplotypes Affect DNA Methylation Levels and Promoter Activity in Breast Carcinomas. Cancer Res. 2008 Jul 15;68(14):5562-71. PubMed PMID: 18632608.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - GSTP1 promoter haplotypes affect DNA methylation levels and promoter activity in breast carcinomas. AU - Rønneberg,Jo Anders, AU - Tost,Jörg, AU - Solvang,Hiroko K, AU - Alnaes,Grethe I G, AU - Johansen,Fredrik E, AU - Brendeford,Elen M, AU - Yakhini,Zohar, AU - Gut,Ivo G, AU - Lønning,Per Eystein, AU - Børresen-Dale,Anne-Lise, AU - Gabrielsen,Odd S, AU - Kristensen,Vessela N, PY - 2008/7/18/pubmed PY - 2008/8/7/medline PY - 2008/7/18/entrez SP - 5562 EP - 71 JF - Cancer research JO - Cancer Res VL - 68 IS - 14 N2 - The CpG island spanning the transcription start of the glutathione S-transferase P1 becomes methylated in a variety of human cancers including breast cancer. To study the effect of sequence variation on hypermethylation of the GSTP1 promoter, we analyzed the genetic and epigenetic variability in 90 tumors from patients with locally advanced breast cancer. High-resolution quantitative analysis revealed large variability in the DNA methylation levels. Lack of methylation was more often observed in the basal and normal-like estrogen receptor (ER)-negative tumors, and methylated GSTP1 was associated with better overall survival (P = 0.00063). Studies of the genetic variation identified 14 different haplotypes. The distribution of methylation levels of tumors homozygous for the most frequent haplotype was significantly different from other haplotype combinations (P = 0.011), the difference being more pronounced in ER-positive (P = 0.005) and progesterone receptor-positive (P = 0.008) tumors. Regression modeling identified the ER status and haplotype as the main determinants of DNA methylation variability. We identified a putative c-Myb response element (MRE) that was present in one of two minimal promoter haplotypes. In vitro analysis showed that c-Myb binds to the MRE, but binding was weakened by the two polymorphisms. Transient cotransfections in luminal-type and basal-like breast cancer cell lines confirmed cell-specific differential binding of c-Myb to the polymorphic sites, leading to a change in the expression from the GSTP1 promoter in vivo. GSTP1 expression was moderately but significantly (P = 0.01) reduced after siRNA-mediated knockdown of c-Myb. Our results indicate that haplotype structure of a promoter is important for the extent of DNA methylation. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/18632608/GSTP1_promoter_haplotypes_affect_DNA_methylation_levels_and_promoter_activity_in_breast_carcinomas_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=18632608 DB - PRIME DP - Unbound Medicine ER -