As a putative etiologic factor for both aging and age-related diseases, oxidative stress is also an attractive mechanistic hypothesis for the biological heterogeneity of estrogen receptor-positive (ER+) human breast cancer. A two-part bioinformatics study was undertaken to understand the interactions between oxidative stress, aging, and the biology and clinical behavior of ER+ human breast cancer. In the first study, expression microarray analysis of 101 age-dichotomized (<45 y; >70 y) early-stage ER+ breast cancers was performed to determine the impact of age-at-diagnosis and PR status on transcriptional regulation. Hierarchical clustering identified six tumor subtypes with a bias in age, but not PR status (p < 0.05). A poor outcome-associated proliferation signature was characteristic of the younger ER+ cohort; while the older cohort showed increased expression of developmental genes and ER, but not ER regulated genes like PR. As well, a 128-gene age signature, but not a similarly derived 80-gene PR signature, was validated in two independent ER+ datasets. In the second study, genes responsive to both oxidant stress and loss of ER function were identified by expression microarray analysis of ER+ MCF7 breast cancer cells treated with three different oxidants. A 62 gene Ox-E/ER signature was identified and associated with development, cancer and cell motility networks. Clinical significance of the Ox-E/ER gene signature and its numeric index was evaluated by microarray and clinical data from 394 ER+ primary human breast cancers. Although unrelated to age-at-diagnosis, Ox-E/ER correlated negatively with PR mRNA levels and PR tumor status, and predicted clinical outcome better than PR. These two studies indicate that: i) confounding age-related gene expression changes may be of greater magnitude than PR-related gene expression differences in ER+ breast cancers, and ii) genes responsive to both oxidative stress and ER function are associated with absent PR expression and worse clinical outcome, indicating that oxidative stress contributes to the development of an aggressive subset of primary ER+ breast cancers.