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Article: Constitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast cancer

TitleConstitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast cancer
Authors
Issue Date2010
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
Plos One, 2010, v. 5 n. 8 How to Cite?
Abstract
Background: The PI3K-Akt signal pathway plays a key role in tumorigenesis and the development of drug-resistance. Cytotoxic chemotherapy resistance is linked to limited therapeutic options and poor prognosis. Methodology/Principal Findings: Examination of FOXO3a and phosphorylated-Akt (P-Akt) expression in breast cancer tissue microarrays showed nuclear FOXO3a was associated with lymph node positivity (p = 0.052), poor prognosis (p = 0.014), and P-Akt expression in invasive ductal carcinoma. Using tamoxifen and doxorubicin-sensitive and -resistant breast cancer cell lines as models, we found that doxorubicin- but not tamoxifen-resistance is associated with nuclear accumulation of FOXO3a, consistent with the finding that sustained nuclear FOXO3a is associated with poor prognosis. We also established that doxorubicin treatment induces proliferation arrest and FOXO3a nuclear relocation in sensitive breast cancer cells. Induction of FOXO3a activity in doxorubicin-sensitive MCF-7 cells was sufficient to promote Akt phosphorylation and arrest cell proliferation. Conversely, knockdown of endogenous FOXO3a expression reduced PI3K/Akt activity. Using MDA-MB-231 cells, in which FOXO3a activity can be induced by 4-hydroxytamoxifen, we showed that FOXO3a induction up-regulates PI3K-Akt activity and enhanced doxorubicin resistance. However FOXO3a induction has little effect on cell proliferation, indicating that FOXO3a or its downstream activity is deregulated in the cytotoxic drug resistant breast cancer cells. Thus, our results suggest that sustained FOXO3a activation can enhance hyperactivation of the PI3K/Akt pathway. Conclusions/Significance: Together these data suggest that lymph node metastasis and poor survival in invasive ductal breast carcinoma are linked to an uncoupling of the Akt-FOXO3a signaling axis. In these breast cancers activated Akt fails to inactivate and re-localize FOXO3a to the cytoplasm, and nuclear-targeted FOXO3a does not induce cell death or cell cycle arrest. As such, sustained nuclear FOXO3a expression in breast cancer may culminate in cancer progression and the development of an aggressive phenotype similar to that observed in cytotoxic chemotherapy resistant breast cancer cell models. © 2010 Chen et al.
Persistent Identifierhttp://hdl.handle.net/10722/137637
ISSN
2013 Impact Factor: 3.534
2013 SCImago Journal Rankings: 1.724
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
University of Hong Kong200807176071
Research Grants Council of Hong KongHKU 767307M
Fundacao para a Ciencia e a Tecnologia (FCT)SFRH/BD/47191/2008
SFRH/BD/44818/2008
Breast Cancer Campaign2007NovPhD16 Lam
Cancer Research UKC37/A5606
Funding Information:

This work was partly funded by grants from the Committee on Research and Conference Grants from the University of Hong Kong (CRCG)(200807176071); the Research Grants Council of Hong Kong General Research Fund (GRF) (HKU 767307M); Fundacao para a Ciencia e a Tecnologia (FCT) (SFRH/BD/47191/2008) (SFRH/BD/44818/2008) (http://alfa.fct.mctes.pt); Breast Cancer Campaign (2007NovPhD16 Lam) (http://www.breastcancercampaign.org); and Cancer Research UK (C37/A5606) (http://www.cancerresearchuk.org). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorChen, Jen_HK
dc.contributor.authorGomes, ARen_HK
dc.contributor.authorMonteiro, LJen_HK
dc.contributor.authorWong, SYen_HK
dc.contributor.authorWu, LHen_HK
dc.contributor.authorNg, TTen_HK
dc.contributor.authorKaradedou, CTen_HK
dc.contributor.authorMillour, Jen_HK
dc.contributor.authorIp, YCen_HK
dc.contributor.authorCheung, YNen_HK
dc.contributor.authorSunters, Aen_HK
dc.contributor.authorChan, KYKen_HK
dc.contributor.authorLam, EWFen_HK
dc.contributor.authorKhoo, USen_HK
dc.date.accessioned2011-08-26T14:30:02Z-
dc.date.available2011-08-26T14:30:02Z-
dc.date.issued2010en_HK
dc.identifier.citationPlos One, 2010, v. 5 n. 8en_HK
dc.identifier.issn1932-6203en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137637-
dc.description.abstractBackground: The PI3K-Akt signal pathway plays a key role in tumorigenesis and the development of drug-resistance. Cytotoxic chemotherapy resistance is linked to limited therapeutic options and poor prognosis. Methodology/Principal Findings: Examination of FOXO3a and phosphorylated-Akt (P-Akt) expression in breast cancer tissue microarrays showed nuclear FOXO3a was associated with lymph node positivity (p = 0.052), poor prognosis (p = 0.014), and P-Akt expression in invasive ductal carcinoma. Using tamoxifen and doxorubicin-sensitive and -resistant breast cancer cell lines as models, we found that doxorubicin- but not tamoxifen-resistance is associated with nuclear accumulation of FOXO3a, consistent with the finding that sustained nuclear FOXO3a is associated with poor prognosis. We also established that doxorubicin treatment induces proliferation arrest and FOXO3a nuclear relocation in sensitive breast cancer cells. Induction of FOXO3a activity in doxorubicin-sensitive MCF-7 cells was sufficient to promote Akt phosphorylation and arrest cell proliferation. Conversely, knockdown of endogenous FOXO3a expression reduced PI3K/Akt activity. Using MDA-MB-231 cells, in which FOXO3a activity can be induced by 4-hydroxytamoxifen, we showed that FOXO3a induction up-regulates PI3K-Akt activity and enhanced doxorubicin resistance. However FOXO3a induction has little effect on cell proliferation, indicating that FOXO3a or its downstream activity is deregulated in the cytotoxic drug resistant breast cancer cells. Thus, our results suggest that sustained FOXO3a activation can enhance hyperactivation of the PI3K/Akt pathway. Conclusions/Significance: Together these data suggest that lymph node metastasis and poor survival in invasive ductal breast carcinoma are linked to an uncoupling of the Akt-FOXO3a signaling axis. In these breast cancers activated Akt fails to inactivate and re-localize FOXO3a to the cytoplasm, and nuclear-targeted FOXO3a does not induce cell death or cell cycle arrest. As such, sustained nuclear FOXO3a expression in breast cancer may culminate in cancer progression and the development of an aggressive phenotype similar to that observed in cytotoxic chemotherapy resistant breast cancer cell models. © 2010 Chen et al.en_HK
dc.languageengen_US
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.subject.meshBreast Neoplasms - diagnosis - genetics - metabolism - pathology-
dc.subject.meshCarcinoma, Ductal - diagnosis - genetics - metabolism - pathology-
dc.subject.meshCell Nucleus - drug effects - metabolism-
dc.subject.meshForkhead Transcription Factors - genetics - metabolism-
dc.subject.meshProto-Oncogene Proteins c-akt - metabolism-
dc.titleConstitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast canceren_HK
dc.typeArticleen_HK
dc.identifier.emailChan, KYK: kelvinc@pathology.hku.hken_HK
dc.identifier.emailKhoo, US: uskhoo@hku.hken_HK
dc.identifier.authorityChan, KYK=rp00453en_HK
dc.identifier.authorityKhoo, US=rp00362en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0012293en_HK
dc.identifier.pmid20808831-
dc.identifier.pmcidPMC2924889-
dc.identifier.scopuseid_2-s2.0-77957924629en_HK
dc.identifier.hkuros191746en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77957924629&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume5en_HK
dc.identifier.issue8en_HK
dc.identifier.spagee12293en_US
dc.identifier.epagee12293en_US
dc.identifier.isiWOS:000281077000007-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectSplicing variant profiling in relation to Estrogen Receptor gene expression in Chinese breast cancer-
dc.identifier.scopusauthoridChen, J=36552004000en_HK
dc.identifier.scopusauthoridGomes, AR=7202386046en_HK
dc.identifier.scopusauthoridMonteiro, LJ=35330377400en_HK
dc.identifier.scopusauthoridWong, SY=7404590342en_HK
dc.identifier.scopusauthoridWu, LH=36553501400en_HK
dc.identifier.scopusauthoridNg, TT=36553020900en_HK
dc.identifier.scopusauthoridKaradedou, CT=15029952600en_HK
dc.identifier.scopusauthoridMillour, J=16033166300en_HK
dc.identifier.scopusauthoridIp, YC=7006740135en_HK
dc.identifier.scopusauthoridCheung, YN=16315128700en_HK
dc.identifier.scopusauthoridSunters, A=6602086611en_HK
dc.identifier.scopusauthoridChan, KYK=7406034195en_HK
dc.identifier.scopusauthoridLam, EWF=7102889877en_HK
dc.identifier.scopusauthoridKhoo, US=7004195799en_HK

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