Abstract
The nitrite synthesis pathway may play a role in breast cancer by activating the estrogen receptor alpha (ERα) through an interaction with the ligand-binding domain of the receptor in the absence of estradiol. ERα plays a significant role in breast tissue proliferation and development, thus mammographic breast density (MBD). As MBD, an established risk factor for breast cancer functions as an intermediate biomarker of breast cancer risk, we investigated the association between polymorphisms in twenty-three genes in the nitrite synthesis pathway and elevated MBD. This study would enable an improved understanding of the role of this pathway in breast cancer etiology and its role in breast cancer risk.We investigated associations between 530 single nucleotide polymorphisms (SNPs) and meant percent breast density (PBD) as a proxy for MBD in two SNP genotype studies of 1400 women enrolled in a cross-sectional study between 2005 and 2011. The study centers were MedStar Georgetown University Hospital and the Georgetown University's Capital Breast Care Center, both in Washington, D.C. In addition, we measured breast density with the user-assisted Cumulus software from the University of Toronto. The generation of SNP genotype data used Illumina's GoldenGate® Genotyping Assay with Veracode technology™ on the BeadXpress reader and Illumina’s global screening array version 3 plus (GSAv3+) on the iScan system. We observed allele-specific associations in a total of twenty SNPs across nine genes in the nitrite synthesis pathway. Study participants with a combination of multiple alleles identified with higher mean PBD had significantly higher mean PBD values than participants with fewer or none of the identified alleles. Our findings support the novel hypothesis that the nitrite synthesis pathway plays a role in breast cancer etiology. Our results highlight the impact on elevated breast density values in participants with several of the identified SNPs associated with mean PBD, thus improving the understanding of how MBD serves as a risk factor for breast cancer. Our results underscore the need to investigate further the role of signaling pathways in breast cancer risk.
