PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects
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Raúl Rincón1,*, Ion Cristóbal1,*, Sandra Zazo2, Oriol Arpí4, Silvia Menéndez4, Rebeca Manso2, Ana Lluch3, Pilar Eroles3, Ana Rovira4, Joan Albanell4, Jesús García-Foncillas1, Juan Madoz-Gúrpide2, Federico Rojo2,4
1Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital “Fundación Jiménez Diaz”, Madrid, Spain
2Pathology Department, IIS “Fundación Jiménez Diaz”, Madrid, Spain
3Institute of Health Research INCLIVA, Valencia, Spain
4Medical Oncology Department, Hospital del Mar, Barcelona, Spain
*These authors have contributed equally to this work
Federico Rojo, e-mail: [email protected]
Keywords: PP2A inhibition, FTY720, prognosis, therapy
Received: August 11, 2014 Accepted: December 31, 2014 Published: January 30, 2015
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.
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