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Article: Adiponectin haploinsufficiency promotes mammary tumor development in MMTV-PyVT mice by modulation of phosphatase and tensin homolog activities

TitleAdiponectin haploinsufficiency promotes mammary tumor development in MMTV-PyVT mice by modulation of phosphatase and tensin homolog activities
Authors
Issue Date2009
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
Plos One, 2009, v. 4 n. 3 How to Cite?
AbstractBackground: Adiponectin is an adipokine possessing beneficial effects on obesity-related medical complications. A negative association of adiponectin levels with breast cancer development has been demonstrated. However, the precise role of adiponectin deficiency in mammary carcinogenesis remains elusive. Methodology/Principal Findings: In the present study, MMTV-polyomavirus middle T antigen (MMTV-PyVT) transgenic mice with reduced adiponectin expressions were established and the stromal effects of adiponectin haploinsufficiency on mammary tumor development evaluated. In mice from both FVB/N and C57BL/6J backgrounds, insufficient adiponectin production promoted mammary tumor onset and development. A distinctive basal-like subtype of tumors, with a more aggressive phenotype, was derived from adiponectin haplodeficient MMTV-PyVT mice. Comparing with those from control MMTV-PyVT mice, the isolated mammary tumor cells showed enhanced tumor progression in re-implanted nude mice, accelerated proliferation in primary cultures, and hyperactivated phosphatidylinositol-3-kinase (PI3K)/Akt/beta-catenin signaling, which at least partly attributed to the decreased phosphatase and tensin homolog (PTEN) activities. Further analysis revealed that PTEN was inactivated by a redox-regulated mechanism. Increased association of PTEN-thioredoxin complexes was detected in tumors derived from mice with reduced adiponectin levels. The activities of thioredoxin (Trx1) and thioredoxin reductase (TrxR1) were significantly elevated, whereas treatment with either curcumin, an irreversible inhibitor of TrxR1, or adiponectin largely attenuated their activities and resulted in the re-activation of PTEN in these tumor cells. Moreover, adiponectin could inhibit TrxR1 promoter-mediated transcription and restore the mRNA expressions of TrxR1. Conclusion: Adiponectin haploinsufficiency facilitated mammary tumorigenesis by down-regulation of PTEN activity and activation of PI3K/ Akt signalling pathway through a mechanism involving Trx1/TrxR1 redox regulations. © 2009 Lam et al.
Persistent Identifierhttp://hdl.handle.net/10722/59133
ISSN
2015 Impact Factor: 3.057
2015 SCImago Journal Rankings: 1.395
ISI Accession Number ID
Funding AgencyGrant Number
University of Hong KongSeeding Funds for Basic Research
Hong Kong Research Grant CouncilHKU 777908M
HKU 779707M
University Grants Committee, HKSARAoE/P-10-01
US National Institutes of HealthHL-51586
Funding Information:

This work was supported by the grants from Seeding Funds for Basic Research of the University of Hong Kong (Y. Wang), Hong Kong Research Grant Council grants HKU 777908M (Y. Wang) and HKU 779707M (A. Xu), and the Area of Excellent Scheme (AoE/P-10-01) established under the University Grants Committee, HKSAR. Adiponectin knockout mice were kindly provided by Dr. Lawrence Chan at Baylor College of Medicine, who generated these mice with the support of the US National Institutes of Health grant HL-51586. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References
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DC FieldValueLanguage
dc.contributor.authorLam, JBBen_HK
dc.contributor.authorChow, KHMen_HK
dc.contributor.authorXu, Aen_HK
dc.contributor.authorLam, KSLen_HK
dc.contributor.authorLiu, Jen_HK
dc.contributor.authorWong, NSen_HK
dc.contributor.authorMoon, RTen_HK
dc.contributor.authorShepard, PRen_HK
dc.contributor.authorCooper, GJSen_HK
dc.contributor.authorWang, Yen_HK
dc.date.accessioned2010-05-31T03:43:31Z-
dc.date.available2010-05-31T03:43:31Z-
dc.date.issued2009en_HK
dc.identifier.citationPlos One, 2009, v. 4 n. 3en_HK
dc.identifier.issn1932-6203en_HK
dc.identifier.urihttp://hdl.handle.net/10722/59133-
dc.description.abstractBackground: Adiponectin is an adipokine possessing beneficial effects on obesity-related medical complications. A negative association of adiponectin levels with breast cancer development has been demonstrated. However, the precise role of adiponectin deficiency in mammary carcinogenesis remains elusive. Methodology/Principal Findings: In the present study, MMTV-polyomavirus middle T antigen (MMTV-PyVT) transgenic mice with reduced adiponectin expressions were established and the stromal effects of adiponectin haploinsufficiency on mammary tumor development evaluated. In mice from both FVB/N and C57BL/6J backgrounds, insufficient adiponectin production promoted mammary tumor onset and development. A distinctive basal-like subtype of tumors, with a more aggressive phenotype, was derived from adiponectin haplodeficient MMTV-PyVT mice. Comparing with those from control MMTV-PyVT mice, the isolated mammary tumor cells showed enhanced tumor progression in re-implanted nude mice, accelerated proliferation in primary cultures, and hyperactivated phosphatidylinositol-3-kinase (PI3K)/Akt/beta-catenin signaling, which at least partly attributed to the decreased phosphatase and tensin homolog (PTEN) activities. Further analysis revealed that PTEN was inactivated by a redox-regulated mechanism. Increased association of PTEN-thioredoxin complexes was detected in tumors derived from mice with reduced adiponectin levels. The activities of thioredoxin (Trx1) and thioredoxin reductase (TrxR1) were significantly elevated, whereas treatment with either curcumin, an irreversible inhibitor of TrxR1, or adiponectin largely attenuated their activities and resulted in the re-activation of PTEN in these tumor cells. Moreover, adiponectin could inhibit TrxR1 promoter-mediated transcription and restore the mRNA expressions of TrxR1. Conclusion: Adiponectin haploinsufficiency facilitated mammary tumorigenesis by down-regulation of PTEN activity and activation of PI3K/ Akt signalling pathway through a mechanism involving Trx1/TrxR1 redox regulations. © 2009 Lam et al.en_HK
dc.languageengen_HK
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.actionen_HK
dc.relation.ispartofPLoS ONEen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.titleAdiponectin haploinsufficiency promotes mammary tumor development in MMTV-PyVT mice by modulation of phosphatase and tensin homolog activitiesen_HK
dc.typeArticleen_HK
dc.identifier.emailChow, KHM: khchowb@hku.hken_HK
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_HK
dc.identifier.emailLam, KSL: ksllam@hku.hken_HK
dc.identifier.emailWong, NS: nswong@hkucc.hku.hken_HK
dc.identifier.emailWang, Y: yuwanghk@hku.hken_HK
dc.identifier.authorityChow, KHM=rp00370en_HK
dc.identifier.authorityXu, A=rp00485en_HK
dc.identifier.authorityLam, KSL=rp00343en_HK
dc.identifier.authorityWong, NS=rp00340en_HK
dc.identifier.authorityWang, Y=rp00239en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0004968en_HK
dc.identifier.scopuseid_2-s2.0-63449118439en_HK
dc.identifier.hkuros156262en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-63449118439&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume4en_HK
dc.identifier.issue3en_HK
dc.identifier.isiWOS:000265499200010-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectAPPL1 as a novel modulator of endothelial nitric oxide production and endothelium-dependent vasodilation-
dc.relation.projectMolecular mechanisms underlying the hepato-protective functions of the fat cell-derived hormone adiponectin: potential roles of uncoupling protein 2-
dc.identifier.scopusauthoridLam, JBB=24448474900en_HK
dc.identifier.scopusauthoridChow, KHM=7202180736en_HK
dc.identifier.scopusauthoridXu, A=7202655409en_HK
dc.identifier.scopusauthoridLam, KSL=8082870600en_HK
dc.identifier.scopusauthoridLiu, J=36066808300en_HK
dc.identifier.scopusauthoridWong, NS=7202836641en_HK
dc.identifier.scopusauthoridMoon, RT=7202316413en_HK
dc.identifier.scopusauthoridShepard, PR=26425291000en_HK
dc.identifier.scopusauthoridCooper, GJS=7402355946en_HK
dc.identifier.scopusauthoridWang, Y=34973733700en_HK

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