The study provides a comprehensive molecular portrait of human breast cancers by integrating data from six different platforms: genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing, and reverse-phase protein arrays. The analysis revealed four main breast cancer classes, each with significant molecular heterogeneity. Somatic mutations in three genes (TP53, PIK3CA, and GATA3) occurred at >10% incidence across all breast cancers, while numerous subtype-associated and novel gene mutations were identified. Two novel protein-expression-defined subgroups were identified, possibly produced by stromal/microenvironmental elements. Specific signaling pathways were identified in each molecular subtype, including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched subtype. Comparison of basal-like breast tumors with high-grade serous ovarian tumors showed many molecular commonalities, suggesting a related etiology and therapeutic opportunities. The findings highlight the hypothesis that much of the clinically observable plasticity and heterogeneity in breast cancer occurs within, rather than across, these major biological subtypes.The study provides a comprehensive molecular portrait of human breast cancers by integrating data from six different platforms: genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing, and reverse-phase protein arrays. The analysis revealed four main breast cancer classes, each with significant molecular heterogeneity. Somatic mutations in three genes (TP53, PIK3CA, and GATA3) occurred at >10% incidence across all breast cancers, while numerous subtype-associated and novel gene mutations were identified. Two novel protein-expression-defined subgroups were identified, possibly produced by stromal/microenvironmental elements. Specific signaling pathways were identified in each molecular subtype, including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched subtype. Comparison of basal-like breast tumors with high-grade serous ovarian tumors showed many molecular commonalities, suggesting a related etiology and therapeutic opportunities. The findings highlight the hypothesis that much of the clinically observable plasticity and heterogeneity in breast cancer occurs within, rather than across, these major biological subtypes.