Abstract
Identifying useful markers of cancer can be problematic due to limited amounts of sample. Some samples such as nipple aspirate fluid (NAF) or early-stage tumors are inherently small. Other samples such as serum are collected in larger volumes but archives of these samples are very valuable and only small amounts of each sample may be available for a single study. Also, given the diverse nature of cancer and the inherent variability in individual protein levels, it seems likely that the best approach to screen for cancer will be to determine the profile of a battery of proteins. As a result, a major challenge in identifying protein markers of disease is the ability to screen many proteins using very small amounts of sample. In this review, we outline some technological advances in proteomics that greatly advance this capability. Specifically, we propose a strategy for identifying markers of breast cancer in NAF that utilizes mass spectrometry (MS) to simultaneously screen hundreds or thousands of proteins in each sample. The best potential markers identified by the MS analysis can then be extensively characterized using an ELISA microarray assay. Because the microarray analysis is quantitative and large numbers of samples can be efficiently analyzed, this approach offers the ability to rapidly assess a battery of selected proteins in a manner that is directly relevant to traditional clinical assays.
Highlights
At present, the best way for most individuals to reduce their overall risk of developing cancer may be changes in lifestyle or diet
1Abbreviations: AMT, accurate mass and time tag; cLC, capillary liquid chromatography; DREAMS, Dynamic Range Enhancement Applied to Mass Spectrometry; Enzymelinked immunosorbent assay (ELISA), enzyme linked immunosorbent assay; Fourier transform ion cyclotron resonance (FTICR), Fourier Transform Ion Cyclotron Resonance; i.d., internal diameter; LCQ, liquid chromatography classic ion trap; MMA, mass measurement accuracy; MS, mass spectrometry; NAF, nipple aspirate fluid; nanoESI, nano-electrospray ionization; PMT, potential mass and time tag; PSA, prostate-selective antigen
NAF is likely to be a concentrated source of protein markers for breast cancer, as this fluid collects proteins from the breast ductal system that is the origin of ∼85% of breast cancer cases
Summary
The best way for most individuals to reduce their overall risk of developing cancer may be changes in lifestyle or diet. In the case of breast cancer, mammography and self-examination have helped to reduce overall mortality rates These examination methods are limited by the size and density of the tumor and are subject to high levels of false positives and negatives. In addition to physical examinations, it is possible to detect cancer by measuring changes in protein levels or other molecular markers of disease. In spite of the limited success of past studies for cancer biomarkers, recent advances in the ability to efficiently screen proteins in complex biological samples have renewed optimism about our ability to find markers of disease. Proteomic methods that employ MS technology can simultaneously analyze hundreds or thousands of proteins that may potentially function as disease markers This lack of bias in the experimental design encourages the identification of new markers of disease. Components in this fluid are thought to be either actively absorbed from plasma by breast cells and transported intracellularly to the ducts, or synthesized within the breast epithelium and directly released into the duct [5, 6]
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