Mechanisms of Cables 1 gene inactivation in human ovarian cancer development.
Cables 1, a cyclin-dependent kinase binding protein, is primarily involved in cell cycle regulation. Loss of nuclear Cables 1 expression is observed in human colon, lung and endometrial cancers. We previously reported that loss of nuclear Cables 1 expression was also observed with high frequency in a limited sample set of human ovarian carcinomas, although the mechanisms underlying loss of nuclear Cables 1 expression remained unknown. Our present objective was to examine Cables 1 expression in ovarian cancer in greater detail, and determine the predominant mechanisms of Cables 1 loss. We assessed potential genetic and epigenetic modifications of the Cables 1 locus through analyses of mutation, polymorphisms, loss of heterozygosity and DNA methylation. We observed a marked loss of nuclear Cables 1 expression in serous and endometrioid ovarian carcinomas that correlated with decreased Cables 1 mRNA levels. Although we detected no Cables 1 mutations, there was evidence of LOH at the Cables 1 locus and epigenetic modification of the Cables 1 promoter region in a subset of ovarian carcinomas and established cancer cell lines. From a functional perspective, over-expression of Cables 1 induced apoptosis, whereas, knockdown of Cables 1 negated this effect. Together these findings suggest that multiple mechanisms underlie the loss of Cables 1 expression in ovarian cancer cells, supporting the hypothesis that Cables 1 is a tumor suppressor in human ovarian cancer.
Sakamoto
Hideo
H
Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, Massachussetts 02114, USA.
Friel
Anne M
AM
Wood
Antony W
AW
Guo
Lankai
L
Ilic
Ana
A
Seiden
Michael V
MV
Chung
Daniel C
DC
Lynch
Maureen P
MP
Serikawa
Takehiro
T
Munro
Elizabeth
E
Oliva
Esther
E
Orsulic
Sandra
S
Kirley
Sandra D
SD
Foster
Rosemary
R
Zukerberg
Lawrence R
LR
Rueda
Bo R
BR
D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002887:Chromosomes, Human, Pair 18; D016213:Cyclins / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D010051:Ovarian Neoplasms / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D025521:Tumor Suppressor Proteins
C486568:CABLES1 protein, human; D002352:Carrier Proteins; D016213:Cyclins; D010750:Phosphoproteins; D025521:Tumor Suppressor Proteins