Proteome profiling of primary mammary epithelial cells derived from MMTV-neu mice revealed that HER2/neu-driven changes in proteome are functionally clustered

Abstract

ERBB2/HER2/NEU receptor tyrosine kinase is overexpressed in 20-30% of human breast cancers and is associated with poor prognosis and an increased metastatic phenotype. MMTV-neu transgenic mice overexpressing NEU in their mammary glands develop tumor after 6 months of age. In an attempt to find a novel protein marker using this mouse model, we identified and characterized the proteins that were differently expressed between primary mammary epithelial cells (PMECs) derived from 2 months old MMTV-neu heterozygote mice and wild type (WT) littermates using a novel proteomics protocols, two-dimensional digest (ChemDigestTM/Trypsin)-LC-MS/MS. We found total 2143 proteins expressed in PMECs from MMTV-neu and WT mice. The differentially expressed proteins were selected and analyzed using DAVID Bioinformatics resource. The proteins involved in anti-apoptosis, purine metabolism, ribosome and proteosome functions were up-regulated while cell adhesion-related proteins were down-regulated in PMECs from MMTV-neu mice as compared to WT PMECs. The results indicate that at least a part of HER2/NEU-driven changes in proteome are clustered into several functional units, not randomly dispersed throughout the proteome, implicating that changes in the expression profiles of individual proteins could be more meaningful with the concomitant changes in the expression profiles of other proteins in the same functional cluster. Our findings also suggest that HER2/NEU-induced intracellular signaling could regulate expression of certain sets of proteins which normally play house-keeping functions like fundamental metabolism or structural scaffold. We hypothesize that these changes in the cellular proteome may be responsible for early onset of HER2/NEU-driven tumorigenesis.