IntroductionIncidence of estrogen receptor (ER)-negative breast cancer, an aggressive tumor subtype associated with worse prognosis, is higher among African American/Black women than other US racial and ethnic groups. The reasons for this disparity remain poorly understood but may be partially explained by differences in the epigenetic landscape.MethodsWe previously conducted genome-wide DNA methylation profiling of ER- breast tumors from Black and White women and identified a large number of differentially methylated loci (DML) by race. Our initial analysis focused on DML mapping to protein-coding genes. In this study, motivated by increasing appreciation for the biological importance of the non-protein coding genome, we focused on 96 DMLs mapping to intergenic and noncoding RNA regions, using paired Illumina Infinium Human Methylation 450K array and RNA-seq data to assess the relationship between CpG methylation and RNA expression of genes located up to 1Mb away from the CpG site.ResultsTwenty-three (23) DMLs were significantly correlated with the expression of 36 genes (FDR<0.05), with some DMLs associated with the expression of single gene and others associated with more than one gene. One DML (cg20401567), hypermethylated in ER- tumors from Black versus White women, mapped to a putative enhancer/super-enhancer element located 1.3 Kb downstream ofHOXB2. Increased methylation at this CpG correlated with decreased expression ofHOXB2(Rho=-0.74, FDR<0.001) and otherHOXB/HOXB-ASgenes. Analysis of an independent set of 207 ER- breast cancers from TCGA similarly confirmed hypermethylation at cg20401567 and reducedHOXB2expression in tumors from Black versus White women (Rho=-0.75, FDR<0.001).DiscussionOur findings indicate that epigenetic differences in ER- tumors between Black and White women are linked to altered gene expression and may hold functional significance in breast cancer pathogenesis.