S100A7 (psoriasin) is highly expressed in preinvasive breast carcinomas and in a subset of poor prognosis invasive tumors. To determine the influence of S100A7 expression on ERalpha negative breast cancer, we profiled mRNA gene expression by Microarray and SAGE analysis, using the ERalpha negative MDA-MB-231 cell line model. Statistically significant transcripts of genes with very high differential expression were further validated by QPCR in both MDA-MB-231 and MDA-MB-468 cell lines expressing exogenous and endogenous S100A7. S100A7 expression correlated with increases in genes associated with MHC class II receptor activity, antigen processing and antigen presentation, and immune cell activation. The transcription factors (TFs) prediction tool CARRIE confirmed an association between TFs reported to be upregulated by S100A7 (NF-kappaB, AP-1, and HIF1) and the regulation of many genes in this dataset. The relationship between S100A7 up-regulation and the MHC class II and HLA-class II molecule coding gene CD74 was examined further in a cohort of ERalpha negative breast tumors by tissue microarray (TMA) and immunohistochemistry (IHC), confirming a significant association in vivo (p=0.042, n=149). These results are consistent with a role for S100A7 in modulating the immune response which may be a factor in early breast tumor progression.