Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer.
OBJECTIVE
This study was designed to elucidate the role of amplification at 8q24 in the pathophysiology of ovarian and breast cancer because increased copy number at this locus is one of the most frequent genomic abnormalities in these cancers.


METHODS
To accomplish this, we assessed the association of amplification at 8q24 with outcome in ovarian cancers using fluorescence in situ hybridization to tissue microarrays and measured responses of ovarian and breast cancer cell lines to specific small interfering RNAs against the oncogene MYC and a putative noncoding RNA, PVT1, both of which map to 8q24.


RESULTS
Amplification of 8q24 was associated with significantly reduced survival duration. In addition, small interfering RNA-mediated reduction in either PVT1 or MYC expression inhibited proliferation in breast and ovarian cancer cell lines in which they were both amplified and overexpressed but not in lines in which they were not amplified/overexpressed. Inhibition of PVT1 expression also induced a strong apoptotic response in cell lines in which it was overexpressed but not in lines in which it was not amplified/overexpressed. Inhibition of MYC, on the other hand, did not induce an apoptotic response in cell lines in which MYC was amplified and overexpressed.


CONCLUSIONS
These results suggest that MYC and PVT1 contribute independently to ovarian and breast pathogenesis when overexpressed because of genomic abnormalities. They also suggest that PVT1-mediated inhibition of apoptosis may explain why amplification of 8q24 is associated with reduced survival duration in patients treated with agents that act through apoptotic mechanisms.
Guan
Yinghui
Y
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
Kuo
Wen-Lin
WL
Stilwell
Jackie L
JL
Takano
Hirokuni
H
Lapuk
Anna V
AV
Fridlyand
Jane
J
Mao
Jian-Hua
JH
Yu
Mamie
M
Miller
Melinda A
MA
Santos
Jennifer L
JL
Kalloger
Steve E
SE
Carlson
Joseph W
JW
Ginzinger
David G
DG
Celniker
Susan E
SE
Mills
Gordon B
GB
Huntsman
David G
DG
Gray
Joe W
JW
D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology*; D002869:Chromosome Aberrations; D002898:Chromosomes, Human, Pair 8; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*; D062085:RNA, Long Noncoding; D014158:Transcription, Genetic; D016896:Treatment Outcome
C521123:PVT1 long-non-coding RNA, human; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding