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ESR1 and EGF genetic variation in relation to breast cancer risk and survival.

ABSTRACT: Oestrogen exposure is a central factor in the development of breast cancer. Oestrogen receptor alpha (ESR1) is the main mediator of oestrogen effect in breast epithelia and has also been shown to be activated by epidermal growth factor (EGF). We sought to determine if common genetic variation in the ESR1 and EGF genes affects breast cancer risk, tumour characteristics or breast cancer survival.We genotyped 157 single nucleotide polymorphisms (SNPs) in ESR1 and 54 SNPs in EGF in 92 Swedish controls and selected haplotype tagging SNPs (tagSNPs) that could predict both single SNP and haplotype variation in the genes with an R2 of at least 0.8. The tagSNPs were genotyped in 1,590 breast cancer cases and 1,518 controls, and their association with breast cancer risk, tumour characteristics and survival were assessed using unconditional logistic regression models, Cox proportional hazard models and haplotype analysis.The single tagSNP analysis did not reveal association evidence for breast cancer risk, tumour characteristics, or survival. A multi-locus analysis of five adjacent tagSNPs suggested a region in ESR1 (between rs3003925 and rs2144025) for association with breast cancer risk (p = 0.001), but the result did not withstand adjustment for multiple comparisons (p = 0.086). A similar region was also implicated by haplotype analyses, but its significance needs to be verified by follow-up analysis.Our results do not support a strong association between common variants in the ESR1 and EGF genes and breast cancer risk, tumour characteristics or survival.

SUBMITTER: Einarsdottir K

PROVIDER: S-EPMC2374971 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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ESR1 and EGF genetic variation in relation to breast cancer risk and survival.

Einarsdóttir Kristjana K Darabi Hatef H Li Yi Y Low Yen Ling YL Li Yu Qing YQ Bonnard Carine C Sjölander Arvid A Czene Kamila K Wedrén Sara S Liu Edison T ET Hall Per P Humphreys Keith K Liu Jianjun J

Breast cancer research : BCR 20080214 1

<h4>Introduction</h4>Oestrogen exposure is a central factor in the development of breast cancer. Oestrogen receptor alpha (ESR1) is the main mediator of oestrogen effect in breast epithelia and has also been shown to be activated by epidermal growth factor (EGF). We sought to determine if common genetic variation in the ESR1 and EGF genes affects breast cancer risk, tumour characteristics or breast cancer survival.<h4>Methods</h4>We genotyped 157 single nucleotide polymorphisms (SNPs) in ESR1 an ...[more]

PMID: 18271972

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Project description:IntroductionGiven the role of estrogen in breast carcinogenesis and the modification of estrogen receptor (ER) activity by its biochemical cofactors, we hypothesize that genetic variation within ER cofactor genes alters cellular response to estrogen exposure and consequently modifies the risk for ER-positive breast cancer.MethodsWe genotyped 790 tagging SNPs within 60 ER cofactor genes in 1,257 cases and 1,464 controls from Sweden and in 2,215 cases and 1,265 controls from Finland, and tested their associations with either ER-positive or ER-negative breast cancer.ResultsSeven SNPs showed consistent association with ER-positive breast cancer in the two independent samples, and six of them were located within PPARGC1B, encoding an ER co-activator, with the strongest association at rs741581 (odds ratio = 1.41, P = 4.84 × 10⁻⁵) that survived Bonferroni correction for multiple testing in the combined ER-positive breast cancer sample (Pcorrected = 0.03). Moreover, we also observed significant synergistic interaction (Pinteraction = 0.008) between the genetic polymorphisms within PPARGC1B and ESR1 in ER-positive breast cancer. By contrast, no consistent association was observed in ER-negative breast cancer. Furthermore, we found that administration of estrogen in the MCF-7 cell line induced PPARGC1B expression and enhanced occupancies of ER and RNA polymerase II within the region of SNP association, suggesting the upregulation of PPARGC1B expression by ESR1 activation.ConclusionsOur study revealed that DNA polymorphisms of PPARGC1B, coding a bona fide ER co-activator, are associated with ER-positive breast cancer risk. The feed-forward transcriptional regulatory loop between PPARGC1B and ESR1 further augments their protein interaction, which provides a plausible mechanistic explanation for the synergistic genetic interaction between PPARGC1B and ESR1 in ER-positive breast cancer. Our study also highlights that biochemically and genomically informed candidate gene studies can enhance the discovery of interactive disease susceptibility genes.

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ESR1 and EGF genetic variation in relation to breast cancer risk and survival.

Publications

ESR1 and EGF genetic variation in relation to breast cancer risk and survival.

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