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Published in: Breast Cancer Research and Treatment 1/2017

01-11-2017 | Preclinical study

Elevated S100A8 protein expression in breast cancer cells and breast tumor stroma is prognostic of poor disease outcome

Authors: P. Miller, K. M. Kidwell, D. Thomas, M. Sabel, J. M. Rae, D. F. Hayes, B. I. Hudson, D. El-Ashry, M. E. Lippman

Published in: Breast Cancer Research and Treatment | Issue 1/2017

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Abstract

Purpose

Elevated S100A8 expression has been observed in cancers of the bladder, esophagus, colon, ovary, and breast. S100A8 is expressed by breast cancer cells as well as by infiltrating immune and myeloid cells. Here we investigate the association of elevated S100A8 protein expression in breast cancer cells and in breast tumor stroma with survival outcomes in a cohort of breast cancer patients.

Patients and methods

Tissue microarrays (TMA) were constructed from breast cancer specimens from 417 patients with stage I–III breast cancer treated at the University of Michigan Comprehensive Cancer Center between 2004 and 2006. Representative regions of non-necrotic tumor and distant normal tissue from each patient were used to construct the TMA. Automated quantitative immunofluorescence (AQUA) was used to measure S100A8 protein expression, and samples were scored for breast cancer cell and stromal S100A8 expression. S100A8 staining intensity was assessed as a continuous value and by exploratory dichotomous cutoffs. Associations between breast cancer cell and stromal S100A8 expression with disease-free survival and overall survival were determined using the Kaplan–Meier method and Cox proportional hazard models.

Results

High breast cancer cell S100A8 protein expression (as indicated by AQUA scores), as a continuous measure, was a significant prognostic factor for OS [univariable hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.00–1.55, p = 0.05] in this patient cohort. Exploratory analyses identified optimal S100A8 AQUA score cutoffs within the breast cancer cell and stromal compartments that significantly separated survival curves for the complete cohort. Elevated breast cancer cell and stromal S100A8 expression, indicated by higher S100A8 AQUA scores, significantly associates with poorer breast cancer outcomes, regardless of estrogen receptor status.

Conclusions

Elevated breast cancer cell and stromal S1008 protein expression are significant indicators of poorer outcomes in early stage breast cancer patients. Evaluation of S100A8 protein expression may provide additional prognostic information beyond traditional breast cancer prognostic biomarkers.
Appendix
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Literature
2.
go back to reference Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, Hallett M, Park M (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14(5):518–527. doi:10.1038/nm1764 CrossRefPubMed Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, Hallett M, Park M (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14(5):518–527. doi:10.​1038/​nm1764 CrossRefPubMed
3.
5.
go back to reference Odink K, Cerletti N, Bruggen J, Clerc RG, Tarcsay L, Zwadlo G, Gerhards G, Schlegel R, Sorg C (1987) Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature 330(6143):80–82. doi:10.1038/330080a0 CrossRefPubMed Odink K, Cerletti N, Bruggen J, Clerc RG, Tarcsay L, Zwadlo G, Gerhards G, Schlegel R, Sorg C (1987) Two calcium-binding proteins in infiltrate macrophages of rheumatoid arthritis. Nature 330(6143):80–82. doi:10.​1038/​330080a0 CrossRefPubMed
6.
go back to reference Ghavami S, Rashedi I, Dattilo BM, Eshraghi M, Chazin WJ, Hashemi M, Wesselborg S, Kerkhoff C, Los M (2008) S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J Leukoc Biol 83(6):1484–1492. doi:10.1189/jlb.0607397 CrossRefPubMedPubMedCentral Ghavami S, Rashedi I, Dattilo BM, Eshraghi M, Chazin WJ, Hashemi M, Wesselborg S, Kerkhoff C, Los M (2008) S100A8/A9 at low concentration promotes tumor cell growth via RAGE ligation and MAP kinase-dependent pathway. J Leukoc Biol 83(6):1484–1492. doi:10.​1189/​jlb.​0607397 CrossRefPubMedPubMedCentral
7.
go back to reference Turovskaya O, Foell D, Sinha P, Vogl T, Newlin R, Nayak J, Nguyen M, Olsson A, Nawroth PP, Bierhaus A, Varki N, Kronenberg M, Freeze HH, Srikrishna G (2008) RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis. Carcinogenesis 29(10):2035–2043. doi:10.1093/carcin/bgn188 CrossRefPubMedPubMedCentral Turovskaya O, Foell D, Sinha P, Vogl T, Newlin R, Nayak J, Nguyen M, Olsson A, Nawroth PP, Bierhaus A, Varki N, Kronenberg M, Freeze HH, Srikrishna G (2008) RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis. Carcinogenesis 29(10):2035–2043. doi:10.​1093/​carcin/​bgn188 CrossRefPubMedPubMedCentral
9.
go back to reference Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna G (2008) Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J Immunol. 181(7):4666–4675CrossRefPubMedPubMedCentral Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna G (2008) Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J Immunol. 181(7):4666–4675CrossRefPubMedPubMedCentral
10.
go back to reference Zaidi AH, Gopalakrishnan V, Kasi PM, Zeng X, Malhotra U, Balasubramanian J, Visweswaran S, Sun M, Flint MS, Davison JM, Hood BL, Conrads TP, Bergman JJ, Bigbee WL, Jobe BA (2014) Evaluation of a 4-protein serum biomarker panel-biglycan, annexin-A6, myeloperoxidase, and protein S100-A9 (B-AMP)-for the detection of esophageal adenocarcinoma. Cancer 120(24):3902–3913. doi:10.1002/cncr.28963 CrossRefPubMedPubMedCentral Zaidi AH, Gopalakrishnan V, Kasi PM, Zeng X, Malhotra U, Balasubramanian J, Visweswaran S, Sun M, Flint MS, Davison JM, Hood BL, Conrads TP, Bergman JJ, Bigbee WL, Jobe BA (2014) Evaluation of a 4-protein serum biomarker panel-biglycan, annexin-A6, myeloperoxidase, and protein S100-A9 (B-AMP)-for the detection of esophageal adenocarcinoma. Cancer 120(24):3902–3913. doi:10.​1002/​cncr.​28963 CrossRefPubMedPubMedCentral
12.
14.
go back to reference Ott HW, Lindner H, Sarg B, Mueller-Holzner E, Abendstein B, Bergant A, Fessler S, Schwaerzler P, Zeimet A, Marth C, Illmensee K (2003) Calgranulins in cystic fluid and serum from patients with ovarian carcinomas. Cancer Res 63(21):7507–7514PubMed Ott HW, Lindner H, Sarg B, Mueller-Holzner E, Abendstein B, Bergant A, Fessler S, Schwaerzler P, Zeimet A, Marth C, Illmensee K (2003) Calgranulins in cystic fluid and serum from patients with ovarian carcinomas. Cancer Res 63(21):7507–7514PubMed
15.
go back to reference Ebbing J, Mathia S, Seibert FS, Pagonas N, Bauer F, Erber B, Gunzel K, Kilic E, Kempkensteffen C, Miller K, Bachmann A, Rosenberger C, Zidek W, Westhoff TH (2014) Urinary calprotectin: a new diagnostic marker in urothelial carcinoma of the bladder. World J Urol 32(6):1485–1492. doi:10.1007/s00345-013-1227-8 CrossRefPubMed Ebbing J, Mathia S, Seibert FS, Pagonas N, Bauer F, Erber B, Gunzel K, Kilic E, Kempkensteffen C, Miller K, Bachmann A, Rosenberger C, Zidek W, Westhoff TH (2014) Urinary calprotectin: a new diagnostic marker in urothelial carcinoma of the bladder. World J Urol 32(6):1485–1492. doi:10.​1007/​s00345-013-1227-8 CrossRefPubMed
16.
go back to reference Drews-Elger K, Iorns E, Dias A, Miller P, Ward TM, Dean S, Clarke J, Campion-Flora A, Rodrigues DN, Reis-Filho JS, Rae JM, Thomas D, Berry D, El-Ashry D, Lippman ME (2014) Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome. Breast Cancer Res Treat 148(1):41–59. doi:10.1007/s10549-014-3122-4 CrossRefPubMed Drews-Elger K, Iorns E, Dias A, Miller P, Ward TM, Dean S, Clarke J, Campion-Flora A, Rodrigues DN, Reis-Filho JS, Rae JM, Thomas D, Berry D, El-Ashry D, Lippman ME (2014) Infiltrating S100A8+ myeloid cells promote metastatic spread of human breast cancer and predict poor clinical outcome. Breast Cancer Res Treat 148(1):41–59. doi:10.​1007/​s10549-014-3122-4 CrossRefPubMed
Metadata
Title
Elevated S100A8 protein expression in breast cancer cells and breast tumor stroma is prognostic of poor disease outcome
Authors
P. Miller
K. M. Kidwell
D. Thomas
M. Sabel
J. M. Rae
D. F. Hayes
B. I. Hudson
D. El-Ashry
M. E. Lippman
Publication date
01-11-2017
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2017
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-017-4366-6

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