PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects.
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- dc.contributor.author Rincón, Raúlca
- dc.contributor.author Cristóbal, Ionca
- dc.contributor.author Zazo, Sandraca
- dc.contributor.author Arpí Llucià, Oriolca
- dc.contributor.author Menendez Romero, Silviaca
- dc.contributor.author Manso, Rebecaca
- dc.contributor.author Lluch, Anaca
- dc.contributor.author Eroles, Pilarca
- dc.contributor.author Rovira Guerín, Anaca
- dc.contributor.author Albanell Mestres, Joanca
- dc.contributor.author García-Foncillas, Jesúsca
- dc.contributor.author Madoz-Gúrpide, Juanca
- dc.contributor.author Rojo, Federicoca
- dc.date.accessioned 2015-11-16T07:52:09Z
- dc.date.available 2015-11-16T07:52:09Z
- dc.date.issued 2015
- dc.description.abstract The protein phosphatase 2A (PP2A) is a key tumor suppressor which has emerged as a novel molecular target in some human cancers. Here, we show that PP2A inhibition is a common event in breast cancer and identified PP2A phosphorylation and deregulation SET and CIP2A as molecular contributing mechanisms to inactivate PP2A. Interestingly, restoration of PP2A activity after FTY720 treatment reduced cell growth, induced apoptosis and decreased AKT and ERK activation. Moreover, FTY720 led to PP2A activation then enhancing doxorubicin-induced antitumor effects both in vitro and in vivo. PP2A inhibition (CPscore: PP2A phosphorylation and/or CIP2A overexpression) was detected in 27% of cases (62/230), and associated with grade (p = 0.017), relapse (p < 0.001), negative estrogen (p < 0.001) and progesterone receptor expression (p < 0.001), HER2-positive tumors (p = 0.049), Ki-67 expression (p < 0.001), and higher AKT (p < 0.001) and ERK (p < 0.001) phosphorylation. Moreover, PP2A inhibition determined shorter overall (p = 0.006) and event-free survival (p = 0.003), and multivariate analysis confirmed its independent prognostic impact. Altogether, our results indicate that PP2A is frequently inactivated in breast cancer and determines worse outcome, and its restoration using PP2A activators represents an alternative therapeutic strategy in this disease.ca
- dc.description.sponsorship This work was supported by PT13/0010/0012, RD12/0036/0051, RD12/0036/0070, PI12/00680, PI12/01421, PI12/01552, SAF2011–26900 grants 524. J.A. and F.R. are recipients of intensification program ISCIII/FEDER. We thank Fundació Cellex (Barcelona) for a generous donation to the Hospital del Mar. R.M. is supported by Fundación Conchita Rábago de Jiménez Díaz.
- dc.format.mimetype application/pdfca
- dc.identifier.citation Rincón R, Cristóbal I, Zazo S, Arpí O, Menéndez S, Manso R. et al. PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects. Oncotarget. 2015 Feb 28;6(6):4299-314. DOI: 10.18632/oncotarget.3012ca
- dc.identifier.doi http://dx.doi.org/10.18632/oncotarget.3012
- dc.identifier.issn 1949-2553
- dc.identifier.uri http://hdl.handle.net/10230/25088
- dc.language.iso engca
- dc.publisher Impact Journalsca
- dc.relation.ispartof Oncotarget. 2015 Feb 28;6(6):4299-314
- dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011–26900
- dc.rights Articles from Oncotarget are provided here courtesy of Impact Journals, LLCca
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.subject.other Mama -- Càncer -- Tractamentca
- dc.title PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects.ca
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/publishedVersionca