Peroxiredoxin-1 protects estrogen receptor a from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer

Hdl Handle:
http://hdl.handle.net/10147/324782
Title:
Peroxiredoxin-1 protects estrogen receptor a from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer
Authors:
O’Leary, Patrick C; Terrile, Marta; Bajor, Malgorzata; Gaj, Pawel; Hennessy, Bryan T; Mills, Gordon B; Zagozdzon, Agnieszka; O’Connor, Darran P; Brennan, Donal J; Connor, Kate; Li, Jane; Gonzalez-Angulo, Ana M; Sun, Han-Dong; Pu, Jian-Xin; Pontén, Fredrik; Uhlén, Mathias; Jirström, Karin; Nowis, Dominika A; Crown, John P; Zagozdzon, Radoslaw; Gallagher, William M
Citation:
O'Leary PC et al. Peroxiredoxin-1 protects estrogen receptor a from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer. Breast Cancer Res. 2014 Jul 10;16(4):R79
Issue Date:
10-Jul-2014
URI:
http://dx.doi.org/10.1186/bcr3691; http://hdl.handle.net/10147/324782
Abstract:
Abstract Introduction Peroxiredoxin-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. Methods An 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. Results In 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. Conclusions PRDX1 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.
Item Type:
Article
Language:
en
Keywords:
BREAST CANCER
Local subject classification:
MOLECULAR BIOLOGY

Full metadata record

DC FieldValue Language
dc.contributor.authorO’Leary, Patrick Cen_GB
dc.contributor.authorTerrile, Martaen_GB
dc.contributor.authorBajor, Malgorzataen_GB
dc.contributor.authorGaj, Pawelen_GB
dc.contributor.authorHennessy, Bryan Ten_GB
dc.contributor.authorMills, Gordon Ben_GB
dc.contributor.authorZagozdzon, Agnieszkaen_GB
dc.contributor.authorO’Connor, Darran Pen_GB
dc.contributor.authorBrennan, Donal Jen_GB
dc.contributor.authorConnor, Kateen_GB
dc.contributor.authorLi, Janeen_GB
dc.contributor.authorGonzalez-Angulo, Ana Men_GB
dc.contributor.authorSun, Han-Dongen_GB
dc.contributor.authorPu, Jian-Xinen_GB
dc.contributor.authorPontén, Fredriken_GB
dc.contributor.authorUhlén, Mathiasen_GB
dc.contributor.authorJirström, Karinen_GB
dc.contributor.authorNowis, Dominika Aen_GB
dc.contributor.authorCrown, John Pen_GB
dc.contributor.authorZagozdzon, Radoslawen_GB
dc.contributor.authorGallagher, William Men_GB
dc.date.accessioned2014-08-14T12:02:55Z-
dc.date.available2014-08-14T12:02:55Z-
dc.date.issued2014-07-10-
dc.identifier.citationO'Leary PC et al. Peroxiredoxin-1 protects estrogen receptor a from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast cancer. Breast Cancer Res. 2014 Jul 10;16(4):R79en_GB
dc.identifier.urihttp://dx.doi.org/10.1186/bcr3691-
dc.identifier.urihttp://hdl.handle.net/10147/324782-
dc.description.abstractAbstract Introduction Peroxiredoxin-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. Methods An 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. Results In 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. Conclusions PRDX1 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.-
dc.language.isoenen
dc.subjectBREAST CANCERen_GB
dc.subject.otherMOLECULAR BIOLOGYen_GB
dc.titlePeroxiredoxin-1 protects estrogen receptor a from oxidative stress-induced suppression and is a protein biomarker of favorable prognosis in breast canceren_GB
dc.typeArticleen
dc.language.rfc3066en-
dc.rights.holderPatrick C O’Leary et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2014-08-11T15:06:32Z-
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