Biology Reference
In-Depth Information
HRR is a common function of BRCA1 and BRCA2.
131
In
support of this concept, recent findings from Nussenz-
weig and colleagues show that knock-out of 53BP1 in
a background of Brca1-/- deletion rescues the HRR
phenotype but not other cellular functions of Brca1
and does not lead to increased tumorigenesis in
mice.
89
BRCA1/2-binding proteins have been identified
that function in HRR and cause familial breast cancer
disease due to mono-allelic mutations in the germ line,
namely PALB2, BRIP1, and RAD51C
.
134-136
The inci-
dence of these mutations is much less than for
BRCA1/2, i.e., accounting only for a few percent of
familial breast cancers. Additional mutations in HRR-
associated genes, i.e., p53, ATM, Chk2, RAD50, NBS1
as well as PTEN, lead to an increased risk of inherited
breast cancer as well.
137
However, whether the HRR
alterations that are associated with all of these mutations
or other cellular effects are responsible for the cancer
predisposition is unknown.
HRR deficiency, chromatid-type chromosomal aberra-
tions, severe ICL hypersensitivity, and impaired forma-
tion of damage-induced RAD51 foci. In the following,
we highlight some of the current data and concepts sup-
porting the presence of HRR defects in sporadic cancers,
which is generally inferred from the presence of defined
genetic mutations in familial cancer syndromes. A better
understanding of the frequency and phenotype of HRR
defects in these tumors will be an important prerequisite
for the development of novel, individualized treatment
strategies.
Breast Cancer
In contrast to familial breast and ovarian cancers,
genetic mutations in BRCA1 or BRCA2 are only rarely
found in sporadic tumors.
139
e
141
Epigenetic gene inacti-
vation is a common alternative to genetic mutation in
the silencing of tumor suppressor genes.
142
Accordingly,
aberrant methylation of the BRCA1 promoter has been
detected in 11
e
14% of sporadic breast cancers.
143
e
145
While BRCA2 hypermethylation appears to be infre-
quent,
146
the BRCA2-associated PALB2/FANCN gene
product was found to be suppressed by promoter hyper-
methylation in 8% of breast and ovarian cancers.
147
Similarly, 19% of sporadic breast cancers stained
completely negative for expression of FANCD2, which
interacts with BRCA2.
148
With regard to the status of
other FA associated genes in sporadic breast cancer
(such as FANCF
149,150
), it is important to point out that
the involvement of FA proteins upstream of FANCD2
in the regulation of HRR remains unclear.
104,151,152
Downregulation of genes known to be involved in
HRR in human cancers does not necessarily imply
a causal role in carcinogenesis. Many observed epige-
netic changes may be secondary phenomena occurring
at a later stage in tumor evolution rather than being
primary pathogenic events.
153
Whether inactivation of
a gene as a primary or secondary event during carcino-
genesis has different effects on HRR levels remains
unknown. Furthermore, it is quite possible that the
initial DNA replication and proliferation defect
conferred by impaired HRR, for example due to
BRCA1 inactivation, triggers compensatory mecha-
nisms to rescue HRR and promote tumor formation
129
(see also below). Thus, the presence of genetic or epige-
netic defects of isolated HRR pathway components may
not necessarily predict a functionally relevant pathway
defect.
Additional support for the presence of HRR defects in
sporadic breast cancer comes from functional studies.
For example, the morphological features and immuno-
histochemical profile of tumors associated with germ
line
BRCA1
mutations show a striking resemblance to
the phenotype of so-called basal-like sporadic breast
cancers.
154
Basal-like cancers are typically characterized
Fanconi Anemia
Fanconi anemia (FA) is a heterogeneous clinical
syndrome characterized by bone marrow failure,
congenital defects, and cancer predisposition.
100,115,138
Cells derived from FA patients exhibit multiple abnor-
malities including chromosomal instability and hyper-
sensitivity to genotoxic agents, particularly drugs that
cause ICLs, such as mitomycin C. The involvement of
FA proteins in the promotion of HRR was described
above. A striking feature of several of the FA genes has
been that they result in FA if mutated in both alleles
but cause breast cancer if the mutation is heterozygous
in the germ-line, i.e., FANCD1/BRCA2, FANCJ/BRIP1,
FANCN/PALB2, FANCO/RAD51C. Notably, these
represent gene products downstream in the FA pathway
that are known to promote HRR. In contrast, breast
cancers are typically not observed in FA patients.
138
Other Syndromes
Table 7.1
lists human cancer predisposition
syndromes, including familial breast cancer and FA, in
which at least part of the phenotype could be ascribed
to faulty HRR (based on Ciccia and Elledge
1
).
HRR Defects in Sporadic Cancer
There is accumulating evidence for the existence of
HRR defects not only in familial cancers but also in
sporadic cancers. This evidence is mainly based on the
observation of mutations or epigenetic alterations in
genes known to be involved in HRR regulation and
repair, such as BRCA1 and BRCA2. In addition, func-
tional analysis of human cancer tissues and cancer cell
lines has revealed in several
instances hallmarks of
