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Oxidatively modified proteins as plasma biomarkers in breast cancer.

ABSTRACT: Post-translational protein modifications (PTMs) are increased in breast tumors.We explored whether PTMs on proteins secreted by the breast could be detected in plasma and potentially used for the early detection of breast cancer.We used a custom ELISA microarray platform to measure 4-hydroxynonenal (HNE), glutathione (GSH), nitrotyrosine and halotyrosine adducts in 27 secreted proteins, for a total of 108 candidate biomarkers. Two independent sets of human plasma samples were measured, for a total of 160 samples. The results were analyzed for consistent cancer-associated changes across the two sample sets. Plasma samples for both cases and benign controls were collected at the time of tissue diagnosis after referral from a positive screen (such as mammography). The results from both studies were evaluated using ANOVA and t-tests or receiver operator curves (ROC).Levels of GSH-modified ceruloplasmin and HNE-modified PDGF were significantly altered in plasma samples from cancer patients relative to benign controls. Healthy controls, which were only included in the first set of samples, were similar to the benign controls for both of these markers. A combination of three glutathionylated proteins produced the best area under the ROC curve, with a value of 76%.Specific PTMs in individual proteins may be useful for distinguishing between women with breast cancer and those with benign breast disease. These oxidative changes in plasma proteins may reflect redox changes in breast cancer. Additional studies on oxidative modifications in individual proteins are warranted.

SUBMITTER: Jin H

PROVIDER: S-EPMC3856946 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Oxidatively modified proteins as plasma biomarkers in breast cancer.

Jin Hongjun H Daly Don S DS Marks Jeffrey R JR Zangar Richard C RC

Cancer biomarkers : section A of Disease markers 20130101 3

<h4>Background</h4>Post-translational protein modifications (PTMs) are increased in breast tumors.<h4>Objective</h4>We explored whether PTMs on proteins secreted by the breast could be detected in plasma and potentially used for the early detection of breast cancer.<h4>Methods</h4>We used a custom ELISA microarray platform to measure 4-hydroxynonenal (HNE), glutathione (GSH), nitrotyrosine and halotyrosine adducts in 27 secreted proteins, for a total of 108 candidate biomarkers. Two independent ...[more]

PMID: 23912491

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Project description:During semen cryopreservation, spermatozoa are exposed to physical and chemical stressors that result in their functional and structural damage. Growing evidence suggests that most cryoinjuries result from oxidative stress accompanying sperm cryopreservation. Elevated amounts of reactive oxygen species (ROS) generated during cryopreservation can react with sperm macromolecules, including proteins. The goal of this study was to investigate the oxidative modifications (measured as carbonylation level changes) of carp spermatozoa proteins triggered by the cryopreservation process. Flow cytometry and computer-assisted sperm analysis were used to evaluate changes in viability, ROS level, and motility of spermatozoa. The spermatozoa proteins that were specifically carbonylated were identified and quantified by Western blotting, in conjunction with 2-dimensional electrophoresis (2D-oxyblot) and matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry. Cryopreservation decreased spermatozoa motility (P < 0.01) and viability (P < 0.0001) and significantly increased (P < 0.0001) the number of ROS-positive cells. We identified 25 protein spots, corresponding to 19 proteins, with increases (P < 0.05) in carbonylation level due to freezing/thawing. The identified proteins are involved in motility, metabolism, calcium-ion binding, signal transduction, protein folding, and intracellular transport. The results suggest that carbonylation of flagellar proteins can result in motility disorders and may contribute to the reduced percentage of motile spermatozoa and disturbances in movement trajectory after sperm cryopreservation. Moreover, cryopreservation may contribute to impaired cellular respiration, ATP regeneration, disturbances of Ca2+ turnover, unfolding of cytoplasmic or histone proteins, disturbances of cell signaling and intracellular transport, and reduced membrane stability. Our results contribute to the knowledge concerning cryoinjury and to further development of a modified cryopreservation procedure aimed at minimizing oxidative damage of carp sperm proteins.

Project description:BackgroundEarly detection of breast cancer in blood is both appealing clinically and challenging technically due to the disease's illusive nature and heterogeneity. Today, even though major breast cancer subtypes have been characterized, i.e., luminal A, luminal B, HER2+, and basal-like, little is known about the heterogeneity of breast cancer in blood, which could help to discover minimally invasive protein biomarkers with which clinical researchers can detect, classify, and monitor different breast cancer subtypes.ResultsIn this study, we performed an integrative pathway-assisted clustering analysis of breast cancer subtypes from plasma proteome samples collected from 80 patients diagnosed with breast cancer and 80 healthy women. First, four breast cancer subtypes and additionally unknown subtype (according to existing annotation) were determined based on pathology lab test results in primary tumors of enrolled patients. Next, we developed and applied four distance metrics, i.e., Protein Intensity, Q-Value, Pathway Profile, and Distance Score Function, to measure and characterize these cancer subtypes. Then, we developed a permutation test to evaluate the significant protein level changes in each biological pathway for each breast cancer subtype, using q-value. Lastly, we developed a pathway-protein matrix for each of the four distance methods to estimate the distance between breast cancer subtypes, for which further Pathway Association Network analysis were performed.ConclusionsWe found that 1) the luminal group (luminal A and luminal B) are clustered together, as well as the basal group (basal-like and HER2+) and 2) luminal A and luminal B are more close to each other than basal-like and HER2+ to each other. Our results were consistent with a recent independent breast cancer research from the Cancer Genome Atlas Network using genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our results showed that changes of different breast cancer subtypes at the pathway level are more profound and less variable than those at the molecular level. Similar subtypes share distinct yet similar pathway activation networks, while dissimilar subtypes are different also at the level of pathway activation networks. The results also showed that distance or similarity of cancer subtypes based on pathway analysis might be able to provide further insight into the intrinsic relationship of breast cancer subtypes. We believe integrative pathway-assisted proteomics analysis described here can become a model for reliable clustering or classification of other cancer subtypes.

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Oxidatively modified proteins as plasma biomarkers in breast cancer.

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Oxidatively modified proteins as plasma biomarkers in breast cancer.

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