Improved diagnostic screening has led to earlier detection of many tumors, but screening may still miss many aggressive tumor types. Proteomic and genomic profiling studies of breast cancer samples have identified tumor markers that may help improve screening for more aggressive, rapidly growing breast cancers. To identify potential blood-based biomarkers for the early detection of breast cancer, we assayed serum samples via matrix-assisted laser desorption ionization–time of flight mass spectrometry from a rat model of mammary carcinogenesis. We found elevated levels of a fragment of the protein dermcidin (DCD) to be associated with early progression of N-methylnitrosourea-induced breast cancer, demonstrating significance at weeks 4 (p = 0.045) and 5 (p = 0.004), a time period during which mammary pathologies rapidly progress from ductal hyperplasia to adenocarcinoma. The highest serum concentrations were observed in rats bearing palpable mammary carcinomas. Increased DCD was also detected with immunoblotting methods in 102 serum samples taken from women just prior to breast cancer diagnosis. To validate these findings in a larger population, we applied a 32-gene in vitro DCD response signature to a dataset of 295 breast tumors and assessed correlation with intrinsic breast cancer subtypes and overall survival. The DCD-derived gene signature was significantly associated with subtype (p < 0.001) and poorer overall survival [HR (95 % CI) = 1.60 (1.01–2.51), p = 0.044]. In conclusion, these results present novel evidence that DCD levels may increase in early carcinogenesis, particularly among more aggressive forms of breast cancer.
Dermcidin Breast cancer Serum Microenvironment
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This work was supported by the National Institutes of Health through the following grants: Women's Health Initiative (U01 CA152637), Early Detection Research Network (N01-WH-74313), and Cardiovascular Health Study (R01-CA116393). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflict of interest
The authors declare that they have no conflict of interest or financial relationship with the organizations that sponsored the research.
Supplemental Fig. 1 (A) Map of DCD sequence and known peptide sequence, brackets indicate unique peptides identified using TOF/TOF methods. (B) Schematic of carboxypeptidase digestion of peak 4452.42 m/z demonstrates each stage of the cleavage, leaving three fragments (4338.32 m/z, 4209.2 m/z, and 4081.03 m/z) that are consistent with the loss of asparagine, glutamic acid and lysine from the C-terminus. The peak of interest identified by MALDI-TOF MS (4209.2 m/z) appeared as an intermediate fragment and the sequence identified is also present in DCD, overlapping with one of the TOF/TOF peptides. (C) Proposed DCD peptide sequence based on molecular weight, TOF/TOF and carboxypeptidase digestion
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