Download BRCA2

Breast Cancer
and BRCA2
•1 million women worldwide
diagnosed.
•1 out of 12 women in Western Europe
and the United States
•30% mortality rate
•Highest cause of death among women
50 to 55 years of age.
http://www.dkfz-heidelberg.de/tumour_genetics/breast.htm
History of BRCA2
•Wooster located the BRCA2 from gene
linkage studies of 15 breast cancer predisposed
families in 1994.
•Hakannsson and Serova sequenced the 10,443
nucleotide gene in 1995.
Simon N Powell,1 and Lisa A Kachnic2
Department of Radiation Oncology, Massachusetts General Hospital, Boston,
MA, USA; 2Department of Radiation Oncology, Boston Medical Center, Boston,
MA, USA
•Knockout mice in embryogenesis
with homozygous loss of function in
Brca2 had high expression of p21,
small growth, and die early in
development.
•Also seen to be sensitive to radiation.
These together implicate possible role
in DNA repair.
P53 prevents
proliferation
if DNA is
damaged.
Theory: BRCA2
mutations lead to other
genes becoming mutant
and tumor formation, ie.
p21 or p53.
www.wellesley.edu/ cancer/adeno-p53.gif
Association of BRCA2 with P53
•In clinical setting there is a high incidence of
inactivation of P53, perhaps greater than 90%.
•Further proof: P53 inactivation partially
rescued developmental arrest in null BRCA2
mice.
•Conclusion: BRCA2 mutations lead to other
genes becoming mutant and tumor formation
ie. p21 or p53.
Overall:
•Genomic instability results
in tumor formation due to
translocations, inversions, etc.
Nature Reviews Molecular Cell Biology 4; 435-445 (2003); doi:10.1038/nrm1127
Homologous Recombination
•Homologous recombination
potential determined by irradiation
sensitivity and sensitivity
to mitomycin C.
•Mitomycin C creates crosslinks that
requires homologous recombination to fix.
•In Brca mutants, there was an increased
sensitivity to Mitomycin C due to loss of
ability to homologous recombination.
Implicates BRCA genes in recombination
role.
Nature Reviews Molecular Cell Biology 4; 435-445 (2003); doi:10.1038/nrm1127
Found:
•Maybe it turns Rad51 on in
pathway. Expressing binding
region to rad51 results in loss of
homologous recombination and
increased sensitivity to radiation.
•BRCA2 binds to ssDNA and helps
RAD51 filament to form.
•This RAD51 filament brings strand of
DNA in for homologous recombination.
Simon N Powell,1 and Lisa A Kachnic2
Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA; 2Department of Radiation
Oncology, Boston Medical Center, Boston, MA, USA
•Not limited to breast cancer
Also linked to:
Male Breast Cancer
Ovarian
Prostatic
Pancreatico biliary
Gastric
Colon
Melanoma
BRCA2 as an indicator
http://www.dkfz-heidelberg.de/tumour_genetics/breast.htm
http://www.dkfz-heidelberg.de/tumour_genetics/breast.htm
Treatment Today:
Lumpectomy: removal of tumor lump.
Partial to total mastectomy: Tumor or breast cut,
chest muscle left intact.
Radical Mastectomy: Chest muscle removed along
with lymph nodes under arms.
All followed with either radiation and/or
chemotherapy.
Tamoxifen: acts against estrogen’s effects and
suppresses growth of tumor. In clinical trials for
effectiveness. Shows increased survival rate.
El Fin
http://www.erudit.org/revue/ms/2002/v18/n11/000456ar.html
Tumor suppressor paradox:
Sporadic: +/+  +/-  -/- all in one cell?
Unlikely
So should be a dominant acting form of BRCA
mutation that keeps rest of w.t. protein from
working in sporadic cases.
Haven’t found it.
Theory: BRCA2 mutations lead to other genes
becoming mutant and tumor formation, ie. p21
or p53.
Treatment options
Overall:
•Brca2 binds to Rad51
•Rad51 brings strand of DNA
in for homologous recombination
•Homologous recombination allows for
DNA repair
•DNA repair prevents genomic instability
Simon N Powell,1 and Lisa A Kachnic2
Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA;
2Department of Radiation Oncology, Boston Medical Center, Boston, MA, USA
Nature Reviews Molecular Cell Biology 4; 435-445 (2003); doi:10.1038/nrm1127
Simon N Powell,1 and Lisa A Kachnic2
Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA; 2Department of
Radiation Oncology, Boston Medical Center, Boston, MA, USA
•Also found inactivation of
p53 partially rescued the
developmental arrest in
Brca2 mice. Further proof
of its role in DNA repair.
mutant tumor suppressor
caused cell cyle arrest due to
truncated C terminal
us recombination allows for DNA repair preventing genomic instability.