Abstract
BackgroundEarly-onset breast cancer (EOBC) affects about one in 300 women aged 40 years or younger and is associated with worse outcomes than later onset breast cancer. This study explored novel serum proteins as surrogate markers of prognosis in patients with EOBC.MethodsSerum samples from EOBC patients (stages 1–3) were analysed using agnostic high-precision quantitative proteomics. Patients received anthracycline-based chemotherapy. The discovery cohort (n = 399) either had more than 5-year disease-free survival (DFS) (good outcome group, n = 203) or DFS of less than 2 years (poor outcome group, n = 196). Expressed proteins were assessed for differential expression between the two groups. Bioinformatics pathway and network analysis in combination with literature research were used to determine clinically relevant proteins. ELISA analysis against an independent sample set from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort (n = 181) was used to validate expression levels of the selected target. Linear and generalized linear modelling was applied to determine the effect of target markers, body mass index (BMI), lymph node involvement (LN), oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 status on patients’ outcome.ResultsA total of 5346 unique proteins were analysed (peptide FDR p ≤ 0.05). Of these, 812 were differentially expressed in the good vs poor outcome groups and showed significant enrichment for the insulin signalling (p = 0.01) and the glycolysis/gluconeogenesis (p = 0.01) pathways. These proteins further correlated with interaction networks involving glucose and fatty acid metabolism. A consistent nodal protein to these metabolic networks was resistin (upregulated in the good outcome group, p = 0.009). ELISA validation demonstrated resistin to be upregulated in the good outcome group (p = 0.04), irrespective of BMI and ER status. LN involvement was the only covariate with a significant association with resistin measurements (p = 0.004). An ancillary in-silico observation was the induction of the inflammatory response, leucocyte infiltration, lymphocyte migration and recruitment of phagocytes (p < 0.0001, z-score > 2). Survival analysis showed that resistin overexpression was associated with improved DFS.ConclusionsHigher circulating resistin correlated with node-negative patients and longer DFS independent of BMI and ER status in women with EOBC. Overexpression of serum resistin in EOBC may be a surrogate indicator of improved prognosis.
Highlights
Early-onset breast cancer (EOBC) affects about one in 300 women aged 40 years or younger and is associated with worse outcomes than later onset breast cancer
ELISA validation demonstrated resistin to be upregulated in the good outcome group (p = 0.04), irrespective of body mass index (BMI) and ER status
Higher circulating resistin correlated with node-negative patients and longer disease-free survival (DFS) independent of BMI and ER status in women with EOBC
Summary
Early-onset breast cancer (EOBC) affects about one in 300 women aged 40 years or younger and is associated with worse outcomes than later onset breast cancer. As a quantitative proteomics approach, the use of chemical labelling with isobaric stable isotope reagents, such as isobaric tags for relative and absolute quantitation (iTRAQ) and tandem mass tags (TMT), has been applied in combination with liquid chromatography–mass spectrometry (LCMS) techniques for the discovery of candidate cancer biomarkers in serum or plasma [4, 5]. Such methodological approaches provide the distinct advantage of simultaneously measuring protein expression under the same instrumental analysis conditions, thereby reducing experimental bias and improving relative quantitative accuracy and precision [6]. Using serum from a cohort study of early-onset breast cancer cases, we explored the potential for quantitative discovery proteomics to reveal novel markers of poor outcome in young women with EOBC [2]
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