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Peroxiredoxin-1 protects estrogen receptor α from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer
O’Leary,Patrick C1; Terrile,Marta1; Bajor,Malgorzata2; Gaj,Pawel2; Hennessy,Bryan T3,4; Mills,Gordon B4; Zagozdzon,Agnieszka1; O’Connor,Darran P1; Brennan,Donal J1; Connor,Kate1; Li,Jane4; Gonzalez-Angulo,Ana Maria5; Sun,Han-Dong6; Pu,Jian-Xin6; Pontén,Fredrik7; Uhlén,Mathias8; Jirstr?m,Karin9; Nowis,Dominika A2,10; Crown,John P11; Zagozdzon,Radoslaw1,2; Gallagher,William M1
2014-07-10
发表期刊Breast Cancer Research
ISSN1465-542X
卷号16期号:4
摘要AbstractIntroductionPeroxiredoxin-1 (PRDX1) is a multifunctional protein, acting as a hydrogen peroxide (H2O2) scavenger, molecular chaperone and immune modulator. Although differential PRDX1 expression has been described in many tumors, the potential role of PRDX1 in breast cancer remains highly ambiguous. Using a comprehensive antibody-based proteomics approach, we interrogated PRDX1 protein as a putative biomarker in estrogen receptor (ER)-positive breast cancer.MethodsAn anti-PRDX1 antibody was validated in breast cancer cell lines using immunoblotting, immunohistochemistry and reverse phase protein array (RPPA) technology. PRDX1 protein expression was evaluated in two independent breast cancer cohorts, represented on a screening RPPA (n?=?712) and a validation tissue microarray (n?=?498). In vitro assays were performed exploring the functional contribution of PRDX1, with oxidative stress conditions mimicked via treatment with H2O2, peroxynitrite, or adenanthin, a PRDX1/2 inhibitor.ResultsIn ER-positive cases, high PRDX1 protein expression is a biomarker of improved prognosis across both cohorts. In the validation cohort, high PRDX1 expression was an independent predictor of improved relapse-free survival (hazard ratio (HR)?=?0.62, 95% confidence interval (CI)?=?0.40 to 0.96, P?=?0.032), breast cancer-specific survival (HR?=?0.44, 95% CI?=?0.24 to 0.79, P?=?0.006) and overall survival (HR?=?0.61, 95% CI?=?0.44 to 0.85, P?=?0.004). RPPA screening of cancer signaling proteins showed that ERα protein was upregulated in PRDX1 high tumors. Exogenous H2O2 treatment decreased ERα protein levels in ER-positive cells. PRDX1 knockdown further sensitized cells to H2O2- and peroxynitrite-mediated effects, whilst PRDX1 overexpression protected against this response. Inhibition of PRDX1/2 antioxidant activity with adenanthin dramatically reduced ERα levels in breast cancer cells.ConclusionsPRDX1 is shown to be an independent predictor of improved outcomes in ER-positive breast cancer. Through its antioxidant function, PRDX1 may prevent oxidative stress-mediated ERα loss, thereby potentially contributing to maintenance of an ER-positive phenotype in mammary tumors. These results for the first time imply a close connection between biological activity of PRDX1 and regulation of estrogen-mediated signaling in breast cancer.
DOI10.1186/bcr3691
语种英语
WOS记录号BMC:10.1186/bcr3691
出版者BioMed Central
引用统计
文献类型期刊论文
条目标识符http://ir.kib.ac.cn/handle/151853/61807
专题中国科学院昆明植物研究所
通讯作者Zagozdzon,Radoslaw; Gallagher,William M
作者单位1.UCD School of Biomolecular and Biomedical Science; Cancer Biology and Therapeutics Laboratory, UCD Conway Institute
2.Medical University of Warsaw; Department of Immunology, Center for Biostructure Research
3.Beaumont Hospital, Royal College of Surgeons in Ireland; Department of Medical Oncology
4.University of Texas M. D. Anderson Cancer Center; Department of Systems Biology
5.University of Texas M.D. Anderson Cancer Center; Department of Breast Medical Oncology
6.Chinese Academy of Sciences, Kunming Botanic Garden; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany
7.Uppsala University; Department of Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskj?ldsv?g 20
8.AlbaNova University Center, Royal Institute of Technology
9.Lund University, Sk?ne University Hospital; Division of Pathology, Department of Clinical Sciences
10.Medical University of Warsaw; Genomic Medicine, Department of General, Transplant and Liver Surgery
11.Dublin City University; Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology
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GB/T 7714
O’Leary,Patrick C,Terrile,Marta,Bajor,Malgorzata,et al. Peroxiredoxin-1 protects estrogen receptor α from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer[J]. Breast Cancer Research,2014,16(4).
APA O’Leary,Patrick C.,Terrile,Marta.,Bajor,Malgorzata.,Gaj,Pawel.,Hennessy,Bryan T.,...&Gallagher,William M.(2014).Peroxiredoxin-1 protects estrogen receptor α from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer.Breast Cancer Research,16(4).
MLA O’Leary,Patrick C,et al."Peroxiredoxin-1 protects estrogen receptor α from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer".Breast Cancer Research 16.4(2014).
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