Amplification and overexpression of PRUNE in human sarcomas and breast carcinomas-a possible mechanism for altering the nm23-H1 activity.
PRUNE, the human homologue of the Drosophila gene, is located in 1q21.3, a region highly amplified in human sarcomas, malignant tumours of mesenchymal origin. Prune protein interacts with the metastasis suppressor nm23-H1, but shows impaired affinity towards the nm23-H1 S120G mutant associated with advanced neuroblastoma. Based on these observations, we previously suggested that prune may act as a negative regulator of nm23-H1 activity. We found amplification of PRUNE in aggressive sarcoma subtypes, such as leiomyosarcomas and malignant fibrous histiocytomas (MFH) as well as in the less malignant liposarcomas. PRUNE amplification was generally accompanied by high mRNA and moderate to high protein levels. The sarcoma samples expressed nm23-H1 mostly at low or moderate levels, whereas mRNA and protein levels were moderate to high in breast carcinomas. For the more aggressive sarcoma subtypes, 9/13 patients with PRUNE amplification developed metastases. A similar situation was observed in all breast carcinomas with amplification of PRUNE. Infection of NIH3T3 cells with a PRUNE recombinant retrovirus increased cell proliferation. Possibly, amplification and overexpression of PRUNE has the same effect in the tumours. We suggest that amplification and overexpression of PRUNE could be a mechanism for inhibition of nm23-H1 activity that affect the development or progression of these tumours.
Forus
A
A
Department of Tumour Biology, The Norwegian Radium Hospital, Oslo, Norway.
D'Angelo
A
A
Henriksen
J
J
Merla
G
G
Maelandsmo
G M
GM
Flørenes
V A
VA
Olivieri
S
S
Bjerkehagen
B
B
Meza-Zepeda
L A
LA
del Vecchio Blanco
F
F
Müller
C
C
Sanvito
F
F
Kononen
J
J
Nesland
J M
JM
Fodstad
Ø
Ø
Reymond
A
A
Kallioniemi
O P
OP
Arrigoni
G
G
Ballabio
A
A
Myklebost
O
O
Zollo
M
M
D016475:3T3 Cells; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D019556:COS Cells; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002455:Cell Division; D029721:Drosophila Proteins; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019476:Insect Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054778:NM23 Nucleoside Diphosphate Kinases; D009362:Neoplasm Metastasis; D009701:Nucleoside-Diphosphate Kinase; D010744:Phosphoric Monoester Hydrolases; D012334:RNA, Neoplasm / Q000096:biosynthesis; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D029721:Drosophila Proteins; D019476:Insect Proteins; D054778:NM23 Nucleoside Diphosphate Kinases; C070996:PN protein, Drosophila; D012334:RNA, Neoplasm; D014157:Transcription Factors; C517938:NME1 protein, human; C517939:Nme1 protein, mouse; D009701:Nucleoside-Diphosphate Kinase; C438732:PRUNE1 protein, human; D010744:Phosphoric Monoester Hydrolases; D020559:Monomeric GTP-Binding Proteins