the role of brca1 in breast cancer ryan allred biol 445 cancer biology spring 2009

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).