It has become increasingly evident that the local microenvironment of breast cancer (BC) plays an important role in its development and progression. A major component of this microenvironment is the extracellular matrix (ECM) that impact tumor progression. We recently identified an ECM gene expression pattern (ECM3) in ~40 % of BCs significantly associated with high risk of relapse only in patients with grade III tumors. To unravel the characteristic of this BC subgroup, in this study we investigated the biomechemical characteristics of ECM3 matrix in human BC samples with different grade. A collagen-reach matrix with several dense areas and a significantly higher value of stiffness distinguished ECM3 grade III tumors from the other breast carcinomas. Proteins recovered from decellularized BC matrices were analyzed by a shotgun label free proteomic approach. Principal Component Analysis on the total matrix proteome showed a significantly different protein repertoire in ECM3 grade III tumors, reflecting a deranged program of matrix biosynthesis in these tumors. A bioinformatic analysis in terms of pathways and GO enrichment focusing on the proteins more expressed or only expressed in ECM3 grade III BCs showed the significant enrichment of molecules involved in the focal adhesion and integrin pathway, ECM-receptor interaction, Tricarboxylic acid (TCA) cycle, ribosome and RNA transport. Obtained results indicate a marked interaction between ECM3 and undifferentiated BC cells that justifies an increased ribosome biogenesis needed at sites where local translation is required as focal adhesions. Moreover, the enrichment in decellularized matrices of molecules implicated in TCA cycle is indicative of a metabolic shift of these carcinomas toward energy production that gives them a selective advantage.