Cancer of the Prostate: Molecular Genetics
199
in many malignancies. Unlike other can-
cers, though, prostate cancer initiation and
progression do not predominantly rely
on oncogenes. As discussed above, ge-
netic losses are much more common than
DNA amplifcation. Nevertheless, region
8q, specifcally 8q24, is the only region to
demonstrate signifcant gain or amplif-
cation (5 to 16%).
MYC
, located at chro-
mosome 8q24, is a member oF the
MYC
proto-oncogene Family.
MYC
encodes a
nuclear DNA-binding phosphoprotein in-
volved in transcriptional regulation and
is Frequently amplifed in breast, lung,
and cervical cancers. Amplifcation, rear-
rangement, and overexpression oF
MYC
has been documented in the LNCaP cell
line but not in primary tumor speci-
mens. Elevated
MYC
expression has been
shown in prostate cancer, compared to
BPH, by Northern blot analysis. Others
have suggested that higher
MYC
levels,
seen with higher grades and lymph node
metastases, correlate with biologic aggres-
siveness. Reporter gene and mobility shiFt
assays demonstrated that c-Myc could re-
press
TMEFF2
gene (a transmembrane
protein that can inhibit prostate cancer
cell growth) expression through its cog-
nate site. In light oF the role oF
TMEFF2
in inhibiting cell growth, its suppression
may contribute to the oncogenic properties
oF c-Myc. Conflicting data From
in situ
hy-
bridization do not confrm any role oF
MYC
in prostate cancer, and additional studies
are required. Another oncogene,
ERBB2
or
HER2/NEU
located at chromosome
17p21, has been studied in prostate cancer.
The proteins in the
ERBB
Family are trans-
membrane receptors with tyrosine kinase
activity, including the
ERBB1
gene en-
coding the epidermal growth Factor (EG±)
receptor.
ERBB2
is implicated in cancers oF
the breast and ovaries and is typically over-
expressed as a result oF gene amplifcation
or transcriptional and posttranscriptional
processing. The results do not clearly show
increased ERBB2 expression in prostate
cancer; some have Found higher protein
expression in prostate cancer, whereas oth-
ers demonstrate overexpression in BPH.
Similarly, the prognostic value oF
ERBB2
amplifcation and P185
NEU
protein ex-
pression is controversial. The fnding oF
P185
NEU
in PIN and carcinoma by im-
munohistochemistry suggests that
ERB
oncogenes may be an early event in
prostate transFormation and provide Fur-
ther evidence For PIN as a pre-neoplastic
state. ±ourteen molecular studies do agree
that
ERBB2
amplifcation is not the mech-
anism oF activation in prostate cancer. As
with P53 studies, technical Factors, such
as method oF antigen retrieval and type oF
antibody used, may signifcantly influence
the results oF immunohistochemical stain-
ing. It has recently been demonstrated
that ±ISH is more sensitive in the de-
tection oF
HER2/NEU
abnormalities, and
Further studies should investigate the use
oF this method. Recent studies suggest that
ErbB1/ErbB2 RTKs play an important role
in the biology oF androgen-independent
prostate cancer and provide a rationale For
clinical evaluation oF inhibitors targeted to
this pathway. Analysis For Her-2 may im-
prove prognostic algorithms For clinically
relevant endpoints other than biochemi-
cal relapse.
The
RAS
oncogene Family is involved
in a wide variety oF human cancers. The
three proteins (H-RAS, K-RAS, and N-
RAS) are guanosine triphosphate binding
proteins essential For signal transduction.
Point mutations within codons 12, 13,
and 61 are the most common activating
changes Found that lead to uncontrolled
cell growth. Immunohistochemistry has
suggested high levels oF RAS expression in
prostate cancer; overexpression correlates
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