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with human cancer, which have been recently dis-
cussed. 205,206 The reported associations of HRR gene
polymorphisms with specific cancers can be easily
reviewed in an on-line NIH data base http://
geneticassociationdb.nih.gov . However, for many of
these polymorphisms, the impact on HRR phenotype
is uncertain and the link to cancer susceptibility is not
robust. A detailed discussion of this controversial field
is beyond the scope of the current text.
Second, there is also emerging evidence that alter-
ations in signal transduction pathways can affect the
HRR machinery. 207 e 210 Genetic or epigenetic alterations
of the phosphatase and tensin homolog (PTEN) gene
have been found in a variety of cancers. 211 In cell lines
studies, PTEN inactivation leads to AKT activation and
has been associated with HRR defects. 209,210,212 The
exact mechanisms by which PTEN may promote HRR
in the various cancer types remain to be identified, but
at least one possibility involves transcriptional regula-
tion of RAD51 expression. 213 These and other data
suggest the presence of crosstalk between cellular signal
transduction pathways and HRR, 214 with important
implications not only for carcinogenesis but also HRR-
directed cancer therapies. However, whether PTEN defi-
ciency is associated with a functionally relevant HRR
defect in human tumors remains to be determined.
Lastly, human tumors frequently contain areas of
hypoxia, both acute due to sudden changes in tissue
blood perfusion as well as chronic due to a distance
from blood vessels that does not support sufficient
oxygen diffusion in tissue. Recent experimental data
indicate that either acute or chronic hypoxia can impair
HRR, potentially through mechanisms such as tran-
scriptional downregulation of RAD51 or suppression
of HRR protein synthesis. 215 e 217 Thus, it will be impor-
tant to identify the presence of defective HRR in hypoxic
tumor regions in patients.
In conclusion, defects in HRR pathways in human
cancers are more common than originally assumed. In
contrast to familial cancers, mutations in HRR genes in
sporadic cancer are relatively infrequent, as appears to
be the case for DNA repair genes in general. 218 The chal-
lenge in this rapidly evolving field is to identify and
characterize HRR alterations as a result of epigenetic
mechanisms as well as changes in signal transduction
pathways and the microenvironment.
carcinogenesis and in identifying HRR defects in human
cancers, the possible presence of upregulated HRR path-
ways in tumors has received much less atten-
tion. 127,129,219 There are two principal reasons as to
why HRR processes may be upregulated in cancer: (1)
Because hyperactive or inappropriate HRR leads to
genomic instability, for example due to normally unwar-
ranted genetic exchanges, or (2) to compensate for an
upstream defect in an HRR regulatory or mediator
protein. 127,129
With regard to the first mechanism, human malignan-
cies and cancer-derived cell lines appear to overexpress
RAD51 frequently. 129,219,220 It has been suggested that
RAD51 overexpression may cause genomic instability
or promote DNA replication during multi-step carcino-
genesis. 129 Consistent with a proliferation-promoting
role, RAD51 protein was strongly expressed in high-
grade prostate cancers, whether sporadic or associated
with BRCA1/2 germ-line mutations. 221 Similarly,
RAD51 expression levels were correlated with tumor
grade in breast cancer. 222 On the other hand, excess
RAD51 can be detrimental to repair and cell growth, at
least in in vitro culture. 223,224 Schild and Wiese 129
recently advanced the model that in some cancers
RAD51 upregulation may constitute an early event
that destabilizes the genome during carcinogenesis.
This model predicts that during later stages of tumor
development there is selection for an HRR defect in an
upstream regulatory protein to counteract the detri-
mental effects of RAD51 overexpression. This concept
is illustrated in Figure 7.5 .
Conversely, RAD51 overexpression may be the conse-
quence of an HRR inactivating event early on during
carcinogenesis. 129 For example, Brca1 bi-allelic knockout
in mice is embryologic lethal and characterized by
a severe growth defect. 132,225 Yet, in carriers of
BRCA1/2 germ line mutations, tumorigenesis requires
loss of the remaining wild-type allele. 226 Thus, mecha-
nisms must exist to overcome the proliferation and repli-
cation deficit associated with loss of BRCA1/2
dependent HR. Accordingly, Bishop and colleagues
described increased expression of RAD51 and its
RAD54 and RAD51AP1 co-factors in BRCA1-mutant
but not BRCA1-proficient breast cancers. 227 In further
experiments using the DT40 chicken model, overexpres-
sion of RAD51 rescued HRR, cell proliferation, and
treatment resistance of BRCA1-deficient cells. Addi-
tional mechanisms that may suppress HRR defects asso-
ciated with dysfunction of BRCA1/2 or other regulatory
proteins are discussed below.
Upregulation of HRR in Cancer
RAD51 Overexpression
HRR levels must be tightly regulated in mitotic cells
to maintain genomic stability (reviewed above). While
there has been great interest in acquiring a better under-
standing of how defective HRR may contribute to
Role of the p53 Tumor Suppressor in Regulation
of RAD51
While the genomic mechanisms by which RAD51
may be overexpressed in tumors are mostly unknown,
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