The progression from normal breast epithelium to a malignant phenotype may depend on changes in genetic events as well as failure of host mechanisms. Intermediate biomarkers are needed to more effectively identify malignant progression as well as to develop the potential for more specific treatments and prevention strategies. The nuclear matrix is the RNA-protein network which forms the skeleton of the nucleus and participates in DNA organization as well as multiple cellular functions. Nuclear matrix proteins have been demonstrated to be tissue and cell type specific as well as to reflect the state of cell differentiation and/or transformation. We prepared nuclear matrices from normal and cancer breast tissue from 10 patients with infiltrating ductal carcinoma of the breast as well as the MCF-10 mortal, immortal, and transfected breast cell lines. Nuclear matrices derived from normal human breast tissue and tumor tissue share common nuclear matrix proteins as well as demonstrate specific changes which appear to occur with the acquisition of the cancer phenotype. The MCF-10 cell lines demonstrate a phenotype that is intermediate between the normal and cancer tissue. These data suggest that the nuclear matrix may be an important biomarker in the pathogenesis of breast cancer.