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.

We genotyped 790 tagging single nucleotide polymorphisms (SNPs) within 60 ER cofactor genes in1257 cases and 1464 controls from Sweden and 2215 cases and 1265 controls from Finland and tested their associations with either ER+ or ER- breast cancer.

Seven SNPs showed consistent association with ER+ 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 (OR=1.41, P=4.84E-05) that survived Bonferroni correction for multiple testing in the combined ER+ 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+ breast cancer. By contrast, no consistent association was observed in ER- 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 up-regulation of PPARGC1B expression by ESR1 activation.

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+ breast cancer. Our study also highlights that biochemically and genomically informed candidate gene studies can enhance the discovery of interactive disease susceptibility genes.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.