Mitogen-activated protein kinase phosphatase-1 in human breast cancer independently predicts prognosis and is repressed by doxorubicin.
OBJECTIVE
Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) dephosphorylates mitogen-activated protein kinase [extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38], mediates breast cancer chemoresistance, and is repressible by doxorubicin in breast cancer cells. We aimed to characterize doxorubicin effects on MKP-1 and phospho-MAPKs in human breast cancers and to further study the clinical relevance of MKP-1 expression in this disease.


METHODS
Doxorubicin effects on MKP-1, phospho-ERK1/2 (p-ERK1/2), phospho-JNK (p-JNK), and phospho-p38 were assayed in a panel of human breast cancer cells by Western blot and in human breast cancer were assayed ex vivo by immunohistochemistry (n = 50). MKP-1 expression was also assayed in a range of normal to malignant breast lesions (n = 30) and in a series of patients (n = 96) with breast cancer and clinical follow-up.


RESULTS
MKP-1 was expressed at low levels in normal breast and in usual ductal hyperplasia and at high levels in in situ carcinoma. MKP-1 was overexpressed in approximately 50% of infiltrating breast carcinomas. Similar to what was observed in breast cancer cell lines, ex vivo exposure of breast tumors to doxorubicin down-regulated MKP-1, and up-regulated p-ERK1/2 and p-JNK, in the majority of cases. However, in a proportion of tumors overexpressing MKP-1, doxorubicin did not significantly affect MKP-1 or phospho-MAPKs. With regard to patient outcome, MKP-1 overexpression was an adverse prognostic factor for relapse both by univariate (P < 0.001) and multivariate analysis (P = 0.002).


CONCLUSIONS
MKP-1 is overexpressed during the malignant transformation of the breast and independently predicts poor prognosis. Furthermore, MKP-1 is repressed by doxorubicin in many human breast cancers.
Rojo
Federico
F
Cancer Research Program, IMIM-Hospital del Mar, Barcelona, Spain.
González-Navarrete
Irene
I
Bragado
Rafael
R
Dalmases
Alba
A
Menéndez
Silvia
S
Cortes-Sempere
Maria
M
Suárez
Cristina
C
Oliva
Cristina
C
Servitja
Sonia
S
Rodriguez-Fanjul
Vanesa
V
Sánchez-Pérez
Isabel
I
Campas
Clara
C
Corominas
Josep Maria
JM
Tusquets
Ignasi
I
Bellosillo
Beatriz
B
Serrano
Sergi
S
Perona
Rosario
R
Rovira
Ana
A
Albanell
Joan
J
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004317:Doxorubicin / Q000494:pharmacology*; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D009364:Neoplasm Recurrence, Local; D010766:Phosphorylation / Q000187:drug effects; D011237:Predictive Value of Tests; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1