Overexpression of the wip1 gene abrogates the p38 MAPK/p53/Wip1 pathway and silences p16 expression in human breast cancers.
Wild-type p53-induced phosphatase (Wip1 or PPM1D) is a serine/threonine protein phosphatase expressed under various stress conditions, which selectively inactivates p38 MAPK. The finding that this gene is amplified in association with frequent gain of 17q21-24 in breast cancers supports its role as a driver oncogene. However, the pathogenetic mechanism of the wip1 gene expression in breast carcinogenesis remains to be elucidated. In this study, we examine Wip1 mRNA and protein expression in 20 breast cancer tissues and six cell lines. We additionally investigate the relationship among Wip1, active p38 MAPK, p53, and p16 proteins. In our experiments, Wip1 mRNA was significantly upregulated in 7 of 20 (35%) invasive breast cancer samples. Overexpression of Wip1 was inversely correlated with that of active (phosphor-) p38 MAPK (P = 0.007). Furthermore, Wip1-overexpressing tumors exhibited no or low levels of p16, which normally accumulates upon p38 MAPK activation (P = 0.057). Loss of p16 expression was not associated with hypermethylation of its promoter or loss of heterozygosity on 9p21. Among the 135 primary breast carcinomas further examined, a significant association was found between the Wip1 overexpression and negative staining for p53 (P value = 0.057), indicating that the tumors are wild-type for p53. This is first report showing that Wip1 overexpression abrogates the homeostatic balance maintained through the p38-p53-Wip1 pathway, and contributes to malignant progression by inactivating wild-type p53 and p38 MAPK as well as decreasing p16 protein levels in human breast tissues.
Yu
Eunsil
E
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-2 dong, Songpa-gu, Seoul 138-736, Korea.
Ahn
Yeon Sun
YS
Jang
Se Jin
SJ
Kim
Mi-Jung
MJ
Yoon
Ho Sung
HS
Gong
Gyungyub
G
Choi
Jene
J
D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D002460:Cell Line; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D019942:Genes, p16 / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C