Abstract 568: Biomarkers of phenethyl isothiocyanate-mediated mammary cancer prevention in MMTV-neu mouse model

Abstract

Abstract Biomarker(s) predictive of efficacy is necessary for clinical development of promising cancer chemopreventive agents because cancer incidence is too rigorous of an end point for malignancies with long latency such as breast cancer. The present study was undertaken to identify biomarker(s) associated with phenethyl isothiocyanate (PEITC)-mediated mammary cancer prevention in MMTV-neu transgenic mouse model. The PEITC is a promising cancer chemopreventive constituent of cruciferous vegetables (e.g., watercress). Two-dimensional gel electrophoresis-mass spectrometry of tumor specimens from control and PEITC-fed mice (n= 3) revealed alterations in expression of several proteins, including hexokinase-1, isoform CRA_f (1.36-fold increase by PEITC administration), L-lactate dehydrogenase A chain isoform 1 (1.57-fold increase by PEITC administration), pyruvate kinase isozymes M1/M2 (1.33-fold decrease by PEITC administration), and mitochondrial ATP synthase, H+ transporting F1 complex beta subunit (1.38-fold decrease by PEITC administration). Interestingly, the PEITC-induced apoptotic cell death in cultured cancer cells is associated with inhibition of oxidative phosphorylation leading to production of reactive oxygen species. Down-regulation of mitochondrial ATP synthase protein in tumors of PEITC-fed mice was confirmed by immunohistochemistry. Expression of mitochondrial ATP synthase was reduced by about 66% in the tumors from PEITC-fed mice in comparison with control (P= 0.05 by two-sided Student's t-test, n= 6-7). In addition, plasma level of transthyretin was significantly higher in the PEITC treatment group compared with control (P= 0.04 by two-sided Student's t-test, n= 5). In conclusion, the present study not only underscores the power of proteomics in cancer chemoprevention research but also suggests that mitochondrial ATP synthase, and possibly hexokinase-1, pyruvate kinase isozymes M1/M2, and/or L-lactate dehydrogenase A chain isoform 1, may be useful biomarkers to assess the biological activity of PEITC in future clinical trials. This study was supported in part by the US PHS grants CA101753 and CA129347, awarded by the National Cancer Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 568. doi:1538-7445.AM2012-568