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

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TitleConstitutively nuclear FOXO3a localization predicts poor survival and promotes Akt phosphorylation in breast cancer
AuthorsChen, J1 3
Gomes, AR3
Monteiro, LJ3
Wong, SY1
Wu, LH1
Ng, TT3
Karadedou, CT3
Millour, J3
Ip, YC1
Cheung, YN1
Sunters, A2 3
Chan, KYK1
Lam, EWF3
Khoo, US1
Issue Date2010
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
CitationPlos One, 2010, v. 5 n. 8 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0012293
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.
ISSN1932-6203
2011 Impact Factor: 4.092
2011 SCImago Journal Rankings: 0.519
DOIhttp://dx.doi.org/10.1371/journal.pone.0012293
PubMed Central IDPMC2924889
ReferencesReferences in Scopus
GrantsSplicing variant profiling in relation to Estrogen Receptor gene expression in Chinese breast cancer
The role of FOXO transcription factors in the development of hormone refractory breast cancer
DC Field
Value
dc.contributor.authorChen, J
dc.contributor.authorGomes, AR
dc.contributor.authorMonteiro, LJ
dc.contributor.authorWong, SY
dc.contributor.authorWu, LH
dc.contributor.authorNg, TT
dc.contributor.authorKaradedou, CT
dc.contributor.authorMillour, J
dc.contributor.authorIp, YC
dc.contributor.authorCheung, YN
dc.contributor.authorSunters, A
dc.contributor.authorChan, KYK
dc.contributor.authorLam, EWF
dc.contributor.authorKhoo, US
dc.date.accessioned2011-08-26T14:30:02Z
dc.date.available2011-08-26T14:30:02Z
dc.date.issued2010
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.
dc.description.grantSplicing variant profiling in relation to Estrogen Receptor gene expression in Chinese breast cancer
dc.description.grantThe role of FOXO transcription factors in the development of hormone refractory breast cancer
dc.description.grantcode96877
dc.description.grantcode99262
dc.description.naturepublished_or_final_version
dc.identifier.citationPlos One, 2010, v. 5 n. 8 [How to Cite?]
DOI: http://dx.doi.org/10.1371/journal.pone.0012293
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0012293
dc.identifier.epagee12293
dc.identifier.hkuros191746
dc.identifier.isiWOS:000281077000007
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.

dc.identifier.issn1932-6203
2011 Impact Factor: 4.092
2011 SCImago Journal Rankings: 0.519
dc.identifier.issue8
dc.identifier.pmcidPMC2924889
dc.identifier.pmid20808831
dc.identifier.scopuseid_2-s2.0-77957924629
dc.identifier.spagee12293
dc.identifier.urihttp://hdl.handle.net/10722/137637
dc.identifier.volume5
dc.languageeng
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
dc.publisher.placeUnited States
dc.relation.ispartofPLoS ONE
dc.relation.referencesReferences in Scopus
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 cancer
dc.typeArticle
Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Royal Veterinary College University of London
  3. Imperial College London