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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, Raúl
dc.contributor.author Cristóbal, Ion
dc.contributor.author Zazo, Sandra
dc.contributor.author Arpí Llucià, Oriol
dc.contributor.author Menendez Romero, Silvia
dc.contributor.author Manso, Rebeca
dc.contributor.author Lluch, Ana
dc.contributor.author Eroles, Pilar
dc.contributor.author Rovira Guerín, Ana
dc.contributor.author Albanell Mestres, Joan
dc.contributor.author García-Foncillas, Jesús
dc.contributor.author Madoz-Gúrpide, Juan
dc.contributor.author Rojo, Federico
dc.date.accessioned 2015-11-16T07:52:09Z
dc.date.available 2015-11-16T07:52:09Z
dc.date.issued 2015
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.3012
dc.identifier.issn 1949-2553
dc.identifier.uri http://hdl.handle.net/10230/25088
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.
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/pdf
dc.language.iso eng
dc.publisher Impact Journals
dc.relation.ispartof Oncotarget. 2015 Feb 28;6(6):4299-314
dc.rights Articles from Oncotarget are provided here courtesy of Impact Journals, LLC
dc.subject.other Mama -- Càncer -- Tractament
dc.title PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects.
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.18632/oncotarget.3012
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011–26900
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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