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Abstract
Studies of the decades-long latent stages of breast carcinogenesis have been limited to when hyperplastic lesions are already present. Investigations of earlier stages of breast cancer (BC) latency have been stymied by the lack of fiducial biomarkers needed to identify where in histologically normal tissues progression toward a BC might be taking place. Recent evidence suggests that a marker of chronic oxidative stress (OxS), protein adducts of 4-hydroxy-2-nonenal (4HNE), can meet this need. Specifically: (1) 4HNE immunopositive (4HNE+) mammary epithelial (ME) cells were found to be prevalent in normal (reduction mammoplasty) tissues of most women (including many teenagers) studied, representative of those living in the United States’ high risk-posing environment and: (2) marked (>1.5-fold) differences were identified between tissues of healthy young women with many vs. few 4HNE+ ME cells in the relative levels of transcripts for 42 of the 84 OxS-associated genes represented in SABioscience Oxidative-Stress/Oxidative-Defense PCR array. Herein we used synchrotron radiation-based Fourier-transform infrared (SR-FTIR) microspectroscopy to identify molecular changes associated with 4HNE adducts in basal and luminal ME cells in terminal ductal units (TDLU), which are the cells of origin of BC, and associated intralobular and interlobular stroma, known contributors to carcinogenesis. Multivariate analysis-derived wavenumbers differentiated 4HNE+ and 4HNE− cells in each of the anatomical compartments. Specifically, principal component and linear discriminant analyses of mid-infrared spectra obtained from these cells revealed unambiguous, statistically highly significant differences in the “biochemical fingerprint” of 4HNE+ vs. 4HNE− luminal and basal ME cells, as well as between associated intralobular and interlobular stroma. These findings demonstrate further SR-FTIR microspectroscopy’s ability to identify molecular changes associated with altered physiological and/or pathophysiological states, in this case with a state of chronic OxS that provides a pro-carcinogenic microenvironment.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interests were disclosed.
Acknowledgments
Funding for these studies in Prof FL Martin’s laboratory was provided by Rosemere Cancer Foundation (II Patel) and BBSRC (SW Fogarty) and in part under a grant from the Pennsylvania Department of Health using Tobacco Settlement Funds (J Weisz). The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. We thank Dr Linda Curtiss, Scripps Research Institute, La Jolla, CA, for the antibody against 4-hydroxy-2-nonenal lysine adducts used in this study. We wish to acknowledge the support of the Department of Obstetrics and Gynecology of the Penn State University College of Medicine that was instrumental in enabling the completion of this study.
Note Added in Proof
This year the Shimadzu Corporation of Japan introduced the first matrix-assisted laser desorption/ionization imaging system with a high enough spatial resolution (5 μm) to enable identifying biomolecules in situ in individual cells or tissue section (http://www.shimadzu.com/about/pressrelease/5iqj1d000001u3r0.html). The system has been tested in the course of its development by researchers at Hamamatsu University School of Medicine, Japan. See references Citation79 and Citation84.