Background: Biological progression of ER+ breast cancer accelerates clinical progression and resistance to treatments. Methods: One laboratory used Affymetrix U133A gene expression microarrays to profile 588 biopsy samples from patients with ER+ breast cancer: 74 AJCC Stage I, 155 Stage IIA, 105 Stage IIB, 127 Stage III, 127 Stage IV (27 at presentation, 100 relapsed). We evaluated stage dependence of ER [ESR1, PGR, sensitivity to endocrine therapy (SET) index], proliferation [MKI67, AURKA, genomic grade index (GGI)], invasion [PLAU (uPA)], PI3-kinase (PIK3CA-GS), VEGF, genomic subtype [PAM50, 3-gene classifier (ESR1, ERBB2, AURKA)], and housekeeper control genes. Significance was evaluated through ordinal median regression (P < 0.002, for multiple testing) after adjusting for staging method (clinical or pathologic). Exploratory Cox regression analyses of progression-free survival (PFS) and overall survival (OS) were performed when treatment was hormonal therapy (HT, N=58) or chemotherapy (CT, N=27) after biopsy of metastatic ER+ breast cancer (MBC). Results: Stage progression was associated with reduced SET index and increased proliferation (GGI, MKI67, AURKA) and metabolism (GAPDH). These changes occurred between Stages IIB and III, and Stages III and IV. Luminal B and proliferation subtypes were more prevalent in Stage IV and less in Stage I. Interestingly, invasion (PLAU) genes were lower in MBC. Only SET index demonstrated a significant interaction with treatment (HT or CT) for MBC (PFS: p=0.018). SET was predictive of PFS and OS following HT, as a continuous score (PFS: HR=0.69, 95%CI 0.49 to 0.97, p=0.035; OS: HR=0.61, 95%CI 0.40 to 0.94, p=0.025) or dichotomized at median value (PFS: HR=0.43, 95%CI 0.24 to 0.76, p=0.003; OS: HR=0.37, 95%CI 0.18 to 0.77, p=0.006). Genomic subtype was prognostic for PFS irrespective of treatment type. High PIK3CA-GS expression predicted OS in the HT subset. Conclusions: Stage progression was associated with decreased ER-related transcription (SET) and increased proliferation, grade, higher risk subtype, and metabolism. In MBC samples, only SET index was predictive of PFS and OS with palliative hormonal therapy.