Cancer of the Prostate: Molecular Genetics
205
Mutations in the E-cadherin gene (
CDH1
)
are rare, suggesting other mechanisms of
regulation and inactivation. Hypermethy-
lation of the 5
0
-CpG islands of
CDH1
may
silence the gene, and this has been found
in E-cadherin–negative cell lines. After
treatment with demethylating agents, E-
cadherin RNA and protein levels were
partially restored. E-cadherin function is
also dependent on sex steroids, which
increase expression, and interaction with
cytoskeletal and other adhesion molecules
such as the catenins. The catenins are
af
am
i
l
yo
ft
h
r
e
e(
α
-,
β
-,
γ
-) proteins
involved in intercellular adhesion and
signal transduction. They associate with
the cytoplasmic domain of E-cadherin
to allow coupling to the microFlament
cytoskeleton. Because of frequent chromo-
some 5q losses and mapping of
α
-catenin
(
CTNNA1)
to chromosome 5q21-q22, they
are of particular interest. The PC-3 cell line
expresses E-cadherin; however,
α
-catenin
is absent owing to homozygous deletion
of the gene. Reexpression of
α
-catenin by
either transfection with
α
-catenin comple-
mentary DNA or transfer of chromosome
5 was associated with a return of cell–cell
contact and decreased tumorigenicity in
mice. Thus, both E-cadherin and
α
-catenin
function is required in reducing inva-
sive potential. Like E-cadherin, loss of
α
-catenin expression, as determined by
immunohistochemistry, predicts invasive-
ness and poor prognosis. ±urther study
is needed of
β
-and
γ
-catenin. Only 5
β
-
catenin mutations in 104 specimens have
been found. In addition, the adenomatous
polyposis gene product (APC) interacts
with
β
-catenin. APC is also located at chro-
mosome 5q21, and inactivation may lead to
altered cell–cell function. Other epithelial
cell-adhesion molecules may act as repres-
sors of growth and invasion. One that
has been evaluated is CCAM, a member
of the immunoglobulin gene superfamily.
CCAM expression in human prostate can-
cer cells reduces anchorage-independent
growth and tumor invasion
in vitro
and
in vivo
respectively. Antisense CCAM ex-
pression in less tumorigenic cell lines was
able to increase tumorigenicity. Studies in
human tissue reveal absence of CCAM
in prostate cancer and decreased staining
in BPH and high-grade PIN. Members
of the integrin family mediate interac-
tions between cells and extracellular matrix
proteins, affecting cell migration, prolifer-
ation, and invasion. These heterodimeric
cell-surface receptors are composed of
noncovalently associated
α
-and
β
-sub
-
units. Overall, downregulation of the var-
ious integrin subunits occurs in prostate
cancer development. These include
α
2,
α
4,
α
5,
α
v, and
β
4. Conversely, increased ex-
pression of integrin
α
6 is associated with
more invasive activity. An increased in-
vasive phenotype in prostate cancer is
associated with
α
3
β
1,
α
4
β
1, and
α
6
β
1.
More recently, it has been found that
α
v
β
3
integrin expression in prostate cancer gen-
erates a migratory phenotype, which is
modulated by a focal adhesion kinase sig-
naling pathway. Other integrins,
α
6
β
4and
α
2
β
1, attach the cells to the basement
membrane and bone matrix, respectively.
The
KAI1
metastasis suppressor gene is
found on chromosome 11p11.2. It belongs
to a family of membrane glycoproteins
and is thought to participate in cell–cell
interaction and cell migration. KAI1 is
expressed in normal human prostate ep-
ithelial cells but is absent in cell lines
derived from metastases, such as DU145,
PC-3, and LNCaP. Reintroduction of the
KAI1
gene into the Dunning rat AT6.1
cell line suppressed the metastatic poten-
tial. Downregulation of KAI1 is found in
the progression of prostate cancer, with
decreased protein expression in 70% of
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