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Increased circulating resistin levels in early-onset breast cancer patients of normalbody mass index correlate with lymphnode negative involvement and longerdisease free survival: a multi-center POSH cohort serum proteomics study

Increased circulating resistin levels in early-onset breast cancer patients of normalbody mass index correlate with lymphnode negative involvement and longerdisease free survival: a multi-center POSH cohort serum proteomics study
Increased circulating resistin levels in early-onset breast cancer patients of normalbody mass index correlate with lymphnode negative involvement and longerdisease free survival: a multi-center POSH cohort serum proteomics study
Background

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. This study explored novel serum proteins as surrogate markers of prognosis in patients with EOBC.

Methods

Serum 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.

Results

A 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-silicoobservation was the induction of the inflammatory response, leucocyte infiltration, lymphocyte migration and recruitment of phagocytes (p < 0.0001z-score > 2). Survival analysis showed that resistin overexpression was associated with improved DFS.

Conclusions

Higher 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.

1465-5411
1-12
Zeidan, Bashar
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Manousopoulou, Antigoni
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Garay Baquero, Diana J.
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White, Cory H.
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Larkin, Samantha E.T.
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Potter, Kathleen N.
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Roumeliotis, Theodoros I.
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Papachristou, Evangelia K.
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Copson, Ellen
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Cutress, Ramsey I.
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Beers, Stephen A.
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Eccles, Diana
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Townsend, Paul A.
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Garbis, Spiros D.
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Zeidan, Bashar
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Manousopoulou, Antigoni
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Garay Baquero, Diana J.
856045e8-eed9-4bbf-9b1c-5985a19d7af3
White, Cory H.
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Larkin, Samantha E.T.
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Potter, Kathleen N.
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Roumeliotis, Theodoros I.
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Papachristou, Evangelia K.
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Copson, Ellen
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Cutress, Ramsey I.
68ae4f86-e8cf-411f-a335-cdba51797406
Beers, Stephen A.
a02548be-3ffd-41ab-9db8-d6e8c3b499a2
Eccles, Diana
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Townsend, Paul A.
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Garbis, Spiros D.
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Zeidan, Bashar, Manousopoulou, Antigoni, Garay Baquero, Diana J., White, Cory H., Larkin, Samantha E.T., Potter, Kathleen N., Roumeliotis, Theodoros I., Papachristou, Evangelia K., Copson, Ellen, Cutress, Ramsey I., Beers, Stephen A., Eccles, Diana, Townsend, Paul A. and Garbis, Spiros D. (2018) Increased circulating resistin levels in early-onset breast cancer patients of normalbody mass index correlate with lymphnode negative involvement and longerdisease free survival: a multi-center POSH cohort serum proteomics study. Breast Cancer Research, 20 (19), 1-12. (doi:10.1186/s13058-018-0938-6).

Record type: Article

Abstract

Background

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. This study explored novel serum proteins as surrogate markers of prognosis in patients with EOBC.

Methods

Serum 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.

Results

A 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-silicoobservation was the induction of the inflammatory response, leucocyte infiltration, lymphocyte migration and recruitment of phagocytes (p < 0.0001z-score > 2). Survival analysis showed that resistin overexpression was associated with improved DFS.

Conclusions

Higher 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.

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More information

Accepted/In Press date: 24 January 2018
e-pub ahead of print date: 22 March 2018
Published date: 2018

Identifiers

Local EPrints ID: 417704
URI: https://eprints.soton.ac.uk/id/eprint/417704
ISSN: 1465-5411
PURE UUID: db8ec733-699d-4ee8-98f2-dafb16764420
ORCID for Diana J. Garay Baquero: ORCID iD orcid.org/0000-0002-9450-8504
ORCID for Spiros D. Garbis: ORCID iD orcid.org/0000-0002-1050-0805

Catalogue record

Date deposited: 12 Feb 2018 17:30
Last modified: 07 Jun 2019 00:32

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Contributors

Author: Bashar Zeidan
Author: Antigoni Manousopoulou
Author: Diana J. Garay Baquero ORCID iD
Author: Cory H. White
Author: Samantha E.T. Larkin
Author: Theodoros I. Roumeliotis
Author: Evangelia K. Papachristou
Author: Ellen Copson
Author: Diana Eccles
Author: Paul A. Townsend

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