Purpose: Hyperactivation of ERK1/2 MAPK (hMAPK) leads to loss of estrogen receptor expression and poor outcome in breast cancer. microRNAs play important regulatory roles and serve as biomarkers of disease. Here we describe molecular, pathological, and clinical outcome associations of an hMAPK-microRNA expression signature in breast cancer. Experimental Design: An hMAPK-microRNA signature was identified, and associations of this signature with molecular and genetic alterations, gene expression, pathological features, and clinical outcomes were determined in primary breast cancers from training data and validated using independent data sets. Univariate and multivariate analyses identified subsignatures associated with increased disease recurrence and poorer disease survival among ER-positive patients, respectively. Results: High-hMAPK-microRNA status significantly correlated with ER-negativity, e nrichment for Basal ,and HER2-subtypes, and reduced recurrence-free and disease-specific survival in publicly available data sets. A robust determination of a recurrence-signature and a survival-signature identified hMAPK-miRNAs commonly associated with poor clinical outcome, and specific subsets associated more closely with either disease recurrence or disease survival, especially among ER+ cancers of both luminal A and luminal B subtypes. Multivariate analyses indicated these recurrence and survival signatures significantly associated with increased risk of disease-specific death and disease recurrence in ER+ cancer and ER+ cancers treated with hormone therapy.