Genetic variation of ESR1 and its co-activator PPARGC1B is synergistic in augmenting the risk of estrogen receptor-positive breast cancer

Yuqing Li, Yi Li, Sara Wedrén, Guoliang Li, Tze Howe Charn, Kartiki Vasant Desai, Carine Bonnard, Kamila Czene, Keith Humphreys, Hatef Darabi, Kristjana Einarsdóttir, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Kee Seng Chia, Heli Nevanlinna, Per Hall, Edison T. Liu, Jianjun Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Citations (Scopus)


Introduction: 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 consequently modifies the risk for ER-positive breast cancer.Methods: We 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.Results: Seven 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 (P corrected = 0.03). Moreover, we also observed significant synergistic interaction (P interaction = 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.Conclusions: Our 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.

Original languageEnglish
Article numberR10
JournalBreast Cancer Research
Issue number1
Publication statusPublished - 26 Jan 2011

Bibliographical note

Funding Information:
The authors are grateful to all of the women who took the time and effort to participate in the present study. They would also like to thank Heng Khai Koon and Ong Eng Hu Jason for genotyping, Frans Verhoeff for processing the genotyping data and the Finnish Cancer Registry for providing cancer data. The present work was supported by funding from the Agency for Science, Technology and Research of Singapore (A_STAR), the Nordic Cancer Union (both for Sweden and Finland) and the Märit and Hans Rausing’s Initiative Against Breast Cancer. In addition, the Finnish study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, and the Sigrid Juselius Foundation.


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