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The Role of BRCA1
in Breast Cancer
Ryan Allred
Biol 445 Cancer Biology
Spring 2009
Breast Cancer One in eight women will
develop breast cancer. 100 times more likely for a
woman to develop breast cancer than a man
Sporadic form ~90% of cases No family history
Hereditary Form 5-10% of cases 25% of cases diagnosed before
age 30 Treatment
Mastectomy, radiation, chemotherapy, hormone therapy
How BRCA1 Was Found Linkage analysis linked
hereditary forms to the long (q) arm of chromosome 17 at position 21
Positional Cloning
Miki, Y et al, 1994.
Structure 1863 amino acids
Carboxyl terminus contains two tandem BRCT repeats Recognized in many DNA repair proteins Could form DNA repair protein complex
RING finger domain Zinc finger which contains a
Cys3HisCys4 amino acid motif which binds two zinc cations.
Involved with protein ubiquitinationwww.pdb.org
Powell and Kachnic, 2003.
Knockout Mice
BRCA1 null embryos Die in developmentp53 growth arrest – associated with DNA damagep53 inactivation partially rescues
Heterozygous mutants normal BRCA1 inactivation late onset breast cancer
Frequent p53 mutations
Tumor Suppressor
Paradox
We still need to figure out the function though.
Let’s Irradiate
Homologous recombination
Ionizing Radiation ExperimentsNo BRCA1 fivefold
reduction in homologous recombination
Correct BRCA1 function normal
Nonhomologous End Joining
More irradiation. Cells deficient in
BRCA1 protein showed defects in the rejoining of fragmented DNA
Other Problems After Ionizing Radiation in BRCA1 deficient cells
DNA synthesis checkpoint defectG2/M checkpoint defect
Transcription coupled repair Apoptosis Ubiquitylation Chromatin remodelling
Immunoflourescent microscopy
BRCA1 and it’s partner
s
Why Breast Cancer?
Estrogen Progesterone Estrogen Receptor Negative Cells?
Proposed - Surrounding cells send pro-survival signals
?BRCA1
Mutations Penetrance of BRCA1 for carriers
Breast Cancer ~80%Ovarian Cancer ~40%
Over 1,000 mutations Loss of heterozygosity Hypermethylation Ring Domain BRCT
Narod et al, 2004.
The Big Picture Defining the
physiological function of BRCA1 has been very complicated
Important for Genomic Integrity
Forms complex that is involved with DNA repair Narod et al, 2004.
References Miki, Y. et al. A strong candidate for the breast and ovarian cancer
susceptibility gene BRCA1. Science 266, 66-71 (1994). Hall, J.M. et al. Linkage of early-onset familial breast cancer to
chromosome 17q21. Science 250, 1684-1689 (1990). Narod, S.A. et al. BRCA1 and BRCA 2:1994 and beyond. Nature Reviews
Vol. 4, 665-674 (2004) Powell, S.N. et al. Roles of BRCA1 and BRCA2 in homologous
recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene 22, 5784-5791 (2003).
Evers, B. et al. Mouse models of BRCA1 and BRCA2 deficiency: past lesson, current understanding and future prospects. Oncogene 25, 5885-5897 (2006).
Tapia T. et al. Promoter hypermethylation of BRCA1 correlates with absence of expression in hereditary breast cancer tumors. Epigenetics 3, 157-163 (2008).
Sankaran S. et al. Identification of domains of BRCA1 critical for the ubiquitin-dependent inhibition of centrosome function. Cancer Research 66, 4100-4107 (2006)
Weinberg R. The Biology of Cancer. Garland Science (2007).