Biomedical Engineering Reference
In-Depth Information
6.3.2.2 Tumor Suppression
The process of carcinogenesis involves alteration in the normal functioning of tumor
suppressor genes. The common gene abnormalities in breast cancer are mutations in
the
p53
gene,
ErbB2/HER2
gene amplification,
c-myc
gene amplification, and
cyclin
D1
gene amplification. Therefore, the gene therapy strategies aimed to correct these
alterations at a genetic level.
6.3.2.2.1 Restoration of the
p53
Function
The
p53
gene is specifically relevant to the development and progression of breast
cancer because
p53
is frequently mutated in breast cancer
[74]
. Because
p53
may
naturally function as an inhibitor of cell proliferation, it inhibits cell growth in most
normal and malignant cells
[75]
. Gene therapy with adenovirus (Ad) controlled by
cytomegalovirus (CMV) promoter has shown promising results against several types
of cancers, including breast cancer, in preclinical studies
[76,77]
.
6.3.2.2.2 Suppression of the HER2 Gene
HER2
(also known as
neu
or c-
erb
B-2) overexpression in breast, ovarian, and head
and neck tumors is known to be the indicator for poor prognosis and poor survival
of these cancer patients
[78,79]
. Therefore, it is desirable to downregulate
HER2/neu
expression in tumor cells. For example, downregulation of
HER2/neu
expression
inhibits cell growth
in vitro
and blocks the development of
HER2/neu
-overexpressing
cancer cells in mouse models, thereby prolonging the survival of treated animals
[80]
.
The expression of the
E1A
gene had been shown to repress the steady-state
HER2
mRNA and protein expression by downregulating
HER2
promoter activity
[81]
. The
results of preclinical studies of Ad5
E1A
gene therapy in
HER2
-overexpressing cancer
led to the development of a phase I clinical trial in a group of patients with advanced
breast and ovarian cancers. The results clearly indicated the feasibility of using
E1A/
3
-[
N
-(
N
,
N
-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol) gene
therapy to treat patients with
HER2
-overexpressing tumors, and the study successfully
proved the working concept developed from preclinical studies
[82]
. Another phase I
trial conducted using
E1A/
DC-Chol caused a subsequent downregulation of
HER-2/
neu
expression and tumor response
[83]
.
6.3.2.2.3 Suppression of c-myc and c-fos Genes
c-myc
and
c-fos
genes are overexpressed especially in breast cancer
[84,85]
. The
transfer of antisense
c-fos
using retrovirus under mammary tumor virus promoter
resulted in the inhibition of breast cancer xenografts in nude mice
[86]
. The encour-
aging results of this study led to the development of a clinical trial of gene therapy
for malignant effusion or meningitis in breast cancer patients who have failed stan-
dard therapy
[87]
.
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