This gene encodes a nuclear phosphoprotein
that plays a role in maintaining genomic stability, and it also acts as a tumor
suppressor. The encoded protein combines with other tumor suppressors, DNA
damage sensors, and signal transducers to form a large multi-subunit protein
complex known as the BRCA1-associated genome surveillance complex (BASC). This
gene product associates with RNA polymerase II, and through the C-terminal
domain, also interacts with histone deacetylase complexes. This protein thus
plays a role in transcription, DNA repair of double-stranded breaks, and
BRCA1 has been implicated in two pathways
of DNA double strand break repair: homologous recombination (HR) and non
homologous end joining (NHEJ). Upon exposure to DNA damaging agents, BRCA1
becomes hyperphosphorylated and is rapidly relocated, along with Rad51, to
sites of DNA synthesis marked by proliferating cell nuclear antigen (PCNA).
Rad51, a homolog of the bacterial RecA, is a central player in HR, catalyzing
the invasion of the single stranded DNA in a homologous duplex and facilitating
the homology search during the establishment of joint molecules. A recent
study, however, has indicated that BRCA1 deficient breast cancer cells
compensate for this deficiency by upregulating Rad51. The resultant HR may be
erroneous and thereby lead to tumorigenesis. In addition, BRCA1 is said to
inhibit the MRN complex which is is implicated in bringing together two DNA
strands together for the error prone NHEJ. BRCA1-deficient cells are sensitive
to ionizing radiation and DNA damaging drugs, such as mitomycin C.
BRCA1 is required for FANCD2 targeting to
sites of DNA damage (see Fanconi-associated genes)
Cells lacking BRCA1 show defects in DNA
repair by homologous recombination.
Defects in BRCA1 are a cause of
susceptibility to breast-ovarian cancer familial type 1 (BROVCA1), a condition
associated with familial predisposition to cancer of the breast and ovaries
(for BROVCA2, see BRCA2; for BROVCA3, see RAD51C). Characteristic features in
affected families are an early age of onset of breast cancer (often before age
50), increased chance of bilateral cancers (cancer that develop in both
breasts, or both ovaries, independently), frequent occurrence of breast cancer
among men, increased incidence of tumors of other specific organs, such as colon
and prostate. BRCA1 carries as many as 1000 different disease associated
mutations, many of which are rare. These mutations are distributed uniformly
along the entire coding region and intronic sequences flanking each exon.
Mutations at more than one locus can be involved in different families or even
in the same case. Mutations in BRCA1 are
at a high penetrance and are thought to be responsible for more than 80% of
inherited breast-ovarian cancer and for 40% of inherited breast cancers.
Defects in BRCA1 are a cause of
susceptibility to ovarian cancer. The lifetime risks of ovarian cancer
associated with a BRCA1 gene mutation carrier has been estimated as 40 to 50%.
Somatic point mutations (deletions,
insertions, substitutions, others) have been observed mostly in breast (2%) and
ovarian (2%) tumors. There are no mutation hotspots.
An increased relative risk to the
development of cancer of the colon, cervix, uterus, pancreas and prostate has
been suggested in BRCA1-mutation carriers.
Oral poly(ADP-ribose) polymerase inhibitor
olaparib shows activity in patients with advanced breast cancer or recurrent
ovarian cancer and BRCA1 or BRCA2 mutations
References (open access):
AKT1/BRCA1 in the control of homologous recombination and genetic
stability: the missing link between hereditary and sporadic breast cancers.
Guirouilh-Barbat JK, Wilhelm T, Lopez BS. Oncotarget. 2010 Dec;1(8):691-9.