PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects
Entity
UAM. Departamento de MedicinaPublisher
Impact JournalsDate
2015-01-30Citation
Oncotarget 6.6 (2015): 4299-4314ISSN
1949-2553Funded by
This work was supported by PT13/0010/0012, RD12/0036/0051, RD12/0036/0070, PI12/00680, PI12/01421, PI12/01552, SAF2011–26900 grants from Instituto de Salud Carlos III, S2010/BMD-2344 from Comunidad de Madrid, 2009 SGR 321 and 2009 SRG 524. J.A. and F.R. are recipients of intensification program ISCIII/FEDERProject
Comunidad de Madrid. S2010/BMD-2344/COLOMICS2Subjects
PP2A inhibition; FTY720; Prognosis; Therapy; MedicinaAbstract
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
Files in this item
Google Scholar:Rincón, Raúl
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Cristóbal, Ion
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Zazo, Sandra
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Arpí, Oriol
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Menéndez, Silvia
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Manso, Rebeca
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Lluch, Ana
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Eroles, Pilar
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Rovira, Ana
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Albanell, Joan
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García-Foncillas López, Jesús Miguel
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Madoz-Gúrpide, Juan
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Rojo, Federico
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