ArticleBreast cancer research : BCR2011
Genetic variation of ESR1 and its co-activator PPARGC1B is synergistic in augmenting the risk of estrogen receptor-positive breast cancer.
Article in Breast cancer research : BCR, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 16 citations in OpenAlex.
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- Identification of the Functions and Prognostic Values of RNA Binding Proteins in Bladder Cancer.Frontiers in genetics · 2021Article
- Exome sequencing in 51 early onset non-familial CRC cases.Molecular genetics & genomic medicine · 2019Article
- DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis.Nature communications · 2018Article
- Promoter methylation of PGC1A and PGC1B predicts cancer incidence in a veteran cohort.Epigenomics · 2018Article
- miR-139 Functions as An Antioncomir to Repress Glioma Progression Through Targeting IGF-1 R, AMY-1, and PGC-1β.Technology in cancer research & treatment · 2017Article
- AMPK Promotes Aberrant PGC1β Expression To Support Human Colon Tumor Cell Survival.Molecular and cellular biology · 2015Article
- ESR1 single nucleotide polymorphisms predict breast cancer susceptibility in the central European Caucasian population.International journal of clinical and experimental medicine · 2013Article
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19 authors at 6 institutions in 4 countries.
Funding
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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.
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