The Role of BRCA1 in Breast Cancer Ryan Allred Biol 445 Cancer Biology Spring 2009
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The Role of BRCA1
in Breast Cancer
Ryan Allred
Biol 445 Cancer Biology
Spring 2009
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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
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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.
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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.
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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
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Tumor Suppressor
Paradox
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We still need to figure out the function though.
Let’s Irradiate
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Homologous recombination
Ionizing Radiation ExperimentsNo BRCA1 fivefold
reduction in homologous recombination
Correct BRCA1 function normal
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Nonhomologous End Joining
More irradiation. Cells deficient in
BRCA1 protein showed defects in the rejoining of fragmented DNA
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Other Problems After Ionizing Radiation in BRCA1 deficient cells
DNA synthesis checkpoint defectG2/M checkpoint defect
Transcription coupled repair Apoptosis Ubiquitylation Chromatin remodelling
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Immunoflourescent microscopy
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BRCA1 and it’s partner
s
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Why Breast Cancer?
Estrogen Progesterone Estrogen Receptor Negative Cells?
Proposed - Surrounding cells send pro-survival signals
?BRCA1
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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.
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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.
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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).