CLINICAL CASES
107
A major cause of familial breast cancer results from mutation in the breast
cancer susceptibility gene,
BRCA1.
Originally identified in 1994, it was not
until 1997 when David Livingston and colleagues demonstrated that
BRCA1
is a nuclear protein that its function began to be understood. They found that
after treatment of cells with agents known to generate DNA damage (i.e.,
hydroxyurea, UV light, ionizing radiation),
BRCA1
was found to localize to
discrete nuclear structures typically called
foci.
Such foci are known to cor-
relate with sites of DNA damage or the sites of stalled replication forks in
S phase of the cell cycle. In addition to the striking nuclear localization of
BRCA1
in response to DNA damaging agents, it was also observed that the
BRCA1 protein was phosphorylated in response to these agents. Given this
and the wealth of data obtained from studying the cell cycle in yeast model
systems, it was concluded that
BRCA1
functioned as a cell cycle regulator in
response to DNA damage.
Further studies have implicated
BRCA1
in the cellular response to DNA
double-stranded breaks (DSBs), a potentially lethal form of DNA damage.
Cells defective in
BRCA1
possess numerous cytological and biological fea-
tures that have been known for years to be correlated with perturbation in the
maintenance of chromosome stability. This includes aneuploidy, centrosome
amplification, spontaneous chromosome breakage, aberrant recombina-
tion events, sensitivity to ionizing radiation, and impaired cell cycle check-
points. In addition, a variety of experiments have demonstrated roles for
BRCA1
in enforcing the G2/M cell cycle transition, homologous recombination
between sister chromatids, as well as the restart of stalled replication in S phase.
The
BRCA1
tumor suppressor interacts with numerous cellular pro-
teins in large complexes. This includes a variety of proteins implicated in var-
ious DNA repair and cell cycle processes. In fact,
BRCA1
has been reported to
interact with as many as 50 proteins! Moreover,
BRCA1
has been shown to
function in various transcriptional mechanisms, suggesting that the function of
this important protein may go well beyond its well-documented role in DSB
repair. How the inactivation of
BRCA1,
a gene that appears to operate in DNA
repair pathways that appear generic to various cell types and predisposes
women to inherited forms of breast cancer, remains a mystery and the subject
of much debate. Given that
BRCA1
appears to have key roles in transcriptional
regulation, it has been suggested that
BRCA1
could influence mammary tissue
through pathways that impinge on the biology of estrogen and estrogen-related
metabolites. In addition, it has been suggested that breast tissue differs from
other tissues in the types of DNA repair processes that are used. Perhaps there
are redundant DNA repair pathways in non-mammary tissue. In any event, the
complex behavior of
BRCA1
promises to challenge future researchers as they
search for the underlying mechanisms that initiate familial breast cancer.
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