Download By Janet Soper and its Effects in Breast Cancer and Ovarian Cancer

and its Effects in
Breast Cancer and
Ovarian Cancer
By Janet Soper
Breast Cancer
211,300 new cases of
invasive breast cancer
in women in 2003
 40,200 deaths from
breast cancer in 2003
 Most frequently
diagnosed non-skin
cancer in women
 Second among cancer
deaths in women

www.dressdownday.ca/
Genetically Predisposed
90% of hereditary
breast cancers have a
mutation in BRCA1 or
BRCA2
 5% of all breast
cancers show a
mutation in BRCA1 or
BRCA2

https://courses.stu.qmul.ac.uk/smd/k
b/humandevelopment/stage2/lectures
/cancergenes/brca-1/brca-1.gif
Specifically, BRCA1 confers…
Risk for ovarian cancer as well as breast cancer
 Earlier age of onset
 80% lifetime risk of cancer- high penetrance
 Distinct tumors from BRCA2 mutations:
invasive, high grade, lymphocyte infiltration

http://www.baylorcme.org/breastcancer/presentation
s/plon/presentation_text.html
What is BRCA 1?
Cloned in 1994 through genetic linkage to
be on chromosome 17
 Expressed in most proliferating cells

http://www.genomenewsnetwork.org/
whats_a_genome/Chp1_2_1.shtml
www.bmm.icnet.uk/
mainimage.html
What does BRCA1 do?

Multitude of roles
have been proposed:
– DNA replication
– cell cycle checkpoint
control
– DNA repair
– regulation of
transcription
– protein ubiquitination
– apoptosis
– chromatin remodeling
wwwermm.cbcu.cam.ac.uk/
01003155h.htm
In knockout mice…



…null for both BRCA1 and BRCA2, embryos died early in
development
showed high levels of cell cycle inhibitor p21
radiation sensitivity and measurable drop in rate of
homologous recombination
http://healthsciences.columbia.edu/news
/journal/images/psjr_170108.gif
Just in the mammary glands
When BRCA1 was
knocked out in just the
mammary glands of
mice, tumors developed.
 When p53 was also
mutated, there were even
more tumors.
 Most tumors in breast
and ovarian cancer(90%)
have inactivated p53.

www.nih.gov/news/pr/ apr99/niddk29.htm
Homologous Recombination

Repair of a
double strand
DNA damage by
breakage of two
homologous
DNA molecules
and strand
exchange
http://www.onk.ns.ac.yu/Archiv
e/Vol11/News-Scheme1.jpg
In Cancer
Tumor suppressor gene
 One copy inherited, the second by LOH
 Heterozygosity is not enough to cause problems
with DSB repair in mutations found thus far
 Why only in breast and ovarian cancer?

– These areas of proliferation naturally incur the most
DNA damage so require the most homologous
recombination
– Expression increases during pregnancy and lactation,
increasing the risk
Mutations

Primarily missense, nonsense, and splice-site
mutations of single amino acids in one of its
binding domains
www.baylorcme.org/.../thumbnails/ plon_026.gif
C-terminus
Two BRCT motifs necessary for protein-protein
binding
 Truncated by insertion or creation of a stop
codon= cancer
 BACH1 has been associated with this domain

gloverlab.biochem.ualberta.ca/ structures.html
BACH1
BRCA1-associated c-terminal helicase
 BRCA1 regulates the cellular location of
BACH1
 Over-expression of mutated BACH1
decreases DNA repair
 Over-expression of mutated BACH1 with
an additional mutation in the BRCA1
binding domain rescues

N-terminus
Ring finger domain
for protein-protein
interaction and E3ubiquitin ligase
activity
 Mutation=cancer and
radiation sensitivity
 Ubiquitination must
be important to DNA
repair and BRCA1
function

http://www.hosppract.com/ge
netics/9710gen.htm
BARD1 and BAP1
Binding to BARD1
(BRCA1-associated
RING domain
protein) increases the
ubiquitination
function of BRCA1
 Also interacts with
BAP1, a ubiquitin
hydrolase

http://www.hosppract.com/genetics/9710g
en.htm
Ubiqui-WHAT??
So it can prevent or promote ubiquitin
mediated protein degradation
 May ubiquintinate each other
 FANCD2

– mono-ubiquitinated in response to DNA
damage
– mutation in this leads to radiation sensitivity
as well
http://www.the-scientist.com/images/yr2003/feb10/brca.gif
How does this cause Cancer?
Resembles p53, which
is mutated in most
cancers
 Makes DNA
maintenance less
secure, allowing more
flaws which can be
tumorigenic

carper.senate.gov/
spotlightbreastcancer.html
Sources
Brody, Lawrence C. and Biesecker, Barbara B. “Breast Cancer: The
High-Risk Mutations”.
http://www.hosppract.com/genetics/9710gen.htm
Cancer Facts and Figures 2003, American Cancer Society
Liu, Yilun and West, Stephen. (2001). “Distinct Functions of BRCA1
and BRCA2 in double strand break”.
http://breastcancer.com/content/4/1/009
Powell, Simon N. and Kachnic, Lisa A. (2003). “Roles of BRCA1 and
BRCA2 in homologous recombination, DNA replication fidelity and
the cellular response to ionizing radiation”. Oncogene, 22,
57845791.