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

P. Miller, K. M. Kidwell, D. Thomas, M. Sabel, J. M. Rae, D. F. Hayes, Barry Hudson, Dorraya El-Ashry, Marc E Lippman

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalBreast Cancer Research and Treatment
DOIs
StateAccepted/In press - Jul 17 2017

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Calgranulin A
Breast Neoplasms
Stromal Cells
Fluorescent Antibody Technique
Survival

Keywords

  • AQUA
  • Automated quantitative immunofluorescence
  • Breast cancer
  • Calprotectin
  • RAGE
  • S100A8
  • S100A9
  • Stroma
  • Tissue microarray

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Elevated S100A8 protein expression in breast cancer cells and breast tumor stroma is prognostic of poor disease outcome. / Miller, P.; Kidwell, K. M.; Thomas, D.; Sabel, M.; Rae, J. M.; Hayes, D. F.; Hudson, Barry; El-Ashry, Dorraya; Lippman, Marc E.

In: Breast Cancer Research and Treatment, 17.07.2017, p. 1-10.

Research output: Contribution to journalArticle

Miller, P. ; Kidwell, K. M. ; Thomas, D. ; Sabel, M. ; Rae, J. M. ; Hayes, D. F. ; Hudson, Barry ; El-Ashry, Dorraya ; Lippman, Marc E. / Elevated S100A8 protein expression in breast cancer cells and breast tumor stroma is prognostic of poor disease outcome. In: Breast Cancer Research and Treatment. 2017 ; pp. 1-10.
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title = "Elevated S100A8 protein expression in breast cancer cells and breast tumor stroma is prognostic of poor disease outcome",
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.",
keywords = "AQUA, Automated quantitative immunofluorescence, Breast cancer, Calprotectin, RAGE, S100A8, S100A9, Stroma, Tissue microarray",
author = "P. Miller and Kidwell, {K. M.} and D. Thomas and M. Sabel and Rae, {J. M.} and Hayes, {D. F.} and Barry Hudson and Dorraya El-Ashry and Lippman, {Marc E}",
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T1 - Elevated S100A8 protein expression in breast cancer cells and breast tumor stroma is prognostic of poor disease outcome

AU - Miller, P.

AU - Kidwell, K. M.

AU - Thomas, D.

AU - Sabel, M.

AU - Rae, J. M.

AU - Hayes, D. F.

AU - Hudson, Barry

AU - El-Ashry, Dorraya

AU - Lippman, Marc E

PY - 2017/7/17

Y1 - 2017/7/17

N2 - 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.

AB - 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.

KW - AQUA

KW - Automated quantitative immunofluorescence

KW - Breast cancer

KW - Calprotectin

KW - RAGE

KW - S100A8

KW - S100A9

KW - Stroma

KW - Tissue microarray

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JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

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