Abstract
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.
Highlights
Given 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 estrogen receptors (ERs) cofactor genes alters cellular response to estrogen exposure and modifies the risk for ER-positive breast cancer
single nucleotide polymorphism (SNP) association analysis First, single SNP association analyses were performed using trend tests in the Swedish and Finnish samples separately by stratifying the cases into ER-positive and ER-negative groups, with 685 SNPs being tested in the Swedish sample and 693 SNPs being tested in the Finnish sample
Our study has revealed an association of genetic variation within PPARGC1B with the risk of ER-positive breast cancer
Summary
Given 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 modifies the risk for ER-positive breast cancer. Through a very large genetic association study, has there been demonstrated a small but significant association of polymorphisms within ESR1 with the risk of breast cancer [9,10,11]. Two plausible explanations for the inconsistent results might be due to the small sample sizes and limited statistical power of these studies, or that the risk was not evaluated by stratifying breast cancer patients based on tumor ER status. The genetic variants within ER cofactors have not been systematically investigated in term of association with breast cancer risk, some coding variants within individual genes, such as NCOA3 and CCND1, have been investigated [12,13,14,15]
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