PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects.
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.
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital "Fundación Jiménez Diaz", Madrid, Spain.
Raúl
R
Rincón
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital "Fundación Jiménez Diaz", Madrid, Spain.
Ion
I
Cristóbal
Pathology Department, IIS "Fundación Jiménez Diaz", Madrid, Spain.
Sandra
S
Zazo
Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
Oriol
O
Arpí
Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
Silvia
S
Menéndez
Pathology Department, IIS "Fundación Jiménez Diaz", Madrid, Spain.
Rebeca
R
Manso
Institute of Health Research INCLIVA, Valencia, Spain.
Ana
A
Lluch
Institute of Health Research INCLIVA, Valencia, Spain.
Pilar
P
Eroles
Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
Ana
A
Rovira
Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
Joan
J
Albanell
Translational Oncology Division, Oncohealth Institute, Health Research Institute FJD-UAM, University Hospital "Fundación Jiménez Diaz", Madrid, Spain.
Jesús
J
García-Foncillas
Pathology Department, IIS "Fundación Jiménez Diaz", Madrid, Spain.
Juan
J
Madoz-Gúrpide
Pathology Department, IIS "Fundación Jiménez Diaz", Madrid, Spain.|Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
Federico
F
Rojo
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D011379:Prognosis; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D016896:Treatment Outcome
D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D004317:Doxorubicin; D054648:Protein Phosphatase 2