Proteomic Study Reveals That Proteins Involved in Metabolic and Detoxification Pathways Are Highly Expressed in HER-2/neu-positive Breast Cancer

Abstract

The receptor tyrosine kinase ErbB2 (HER-2/neu) is overexpressed in up to 30% of breast cancers and is associated with poor prognosis and an increased likelihood of metastasis especially in node-positive tumors. In this proteomic study, to identify the proteins that are associated with the aggressive phenotype of HER-2/neu-positive breast cancer, tumor cells from both HER-2/neu-positive and -negative tumors were procured by laser capture microdissection. Differentially expressed proteins in the two subsets of tumors were identified by two-dimensional electrophoresis and MALDI-TOF/TOF MS/MS. We found differential expression of several key cell cycle modulators, which were linked with increased proliferation of the HER-2/neu-overexpressing cells. Nine proteins involved in glycolysis (triose-phosphate isomerase (TPI), phosphoglycerate kinase 1 (PGK1), and enolase 1 (ENO1)), lipid synthesis (fatty acid synthase ( Traditional cancer chemotherapy agents designed to block cell division are toxic to healthy cells as well as to cancer cells. Targeting specific metabolic pathways to stop cancer growth is potentially less toxic to normal cells and can improve tolerability considerably. Thus, anticancer drug discovery has shifted from the traditional empiric random screening approach to a more rational and mechanistic, target-based approach whereby specific abnormalities in cell functioning are modulated in a classical drug (ligand)-receptor fashion. The HER/ErbB family of transmembrane receptors is one of the most exciting targets currently under evaluation.This ErbB family of receptor tyrosine kinases includes four closely related members: HER-1/ErbB1 (also known as the epidermal growth factor receptor), HER-2/ErbB2 (also known as HER-2/neu), 1 HER-3/ErbB3, and HER-4/ErbB4. These receptors initiate signals by forming ligand-induced combinations of homo-and heterodimers (1) and play a critical role in the pathogenesis of breast cancer. HER-2/neu, one of the most well characterized breast cancer oncogenes, is amplified in about 20 -30% of all human breast cancers (2, 3) and is also overexpressed in a variety of other human tumors, including ovarian, lung, gastric, and oral cancers. It appears

Differential tissue-specific protein markers of vaginal carcinoma

“…Prolyl-4-hydrolase beta-isoform (P4HB) was found to be upregulated in HER-2/neu-positive breast tumours (Zhang et al, 2005a) in contrast to our findings.…”

Overexpression of LASP-1 mediates migration and proliferation of human ovarian cancer cells and influences zyxin localisation

“…In addition, pyruvat kinase has been identified as a proteomic marker of cancer progression in breast cancer (Isidoro et al, 2005). The glycolytic enzyme enolase-1 as well as HSP27, two additional proteins identified in the 2D-gel experiments, are associated with high metastatic activity in breast cancer cells (Espana et al, 2005;Zhang et al, 2005).…”

Pharmacological blockade of Fatty Acid Synthase (FASN) reverses acquired autoresistance to trastuzumab (Herceptin™) by transcriptionally inhibiting ‘HER2 super-expression’ occurring in high-dose trastuzumab-conditioned SKBR3/Tzb100 breast cancer cells

“…Considering that high levels of FASN expression have recently been positively related to HER2 overexpression in breast cancer specimens (34,35), a promising therapeutic approach against HER2-overexpressing breast carcinomas may combine FASN blockers, which could repress HER2 oncogene expression at the transcriptional level, and monoclonal antibodies to HER2, which target the ecto-domain of HER2 and promote its degradation (29). We here hypothesized that FASN-regulated activity of the endogenous HER2 gene promoter may represent an anti-HER2 strategy that should not be affected by the upstream mechanisms of resistance previously described for Tzb-based anti-HER2 immunotherapy (15)(16)(17)(18).…”