BRCA1The First Breast Cancer

Gene

Presentation By Liz Mosley

BRCA1 in Breast Cancer

• Breast cancer is the most common cancer in women (1 in 8)1

• Hereditary breast cancer accounts for 10 % of those cases 2

• BRCA1 mutations are the most common cause of hereditary breast cancer 2

• BRCA1-mutated breast cancers tend to be more aggressive 3

• A mutation in BRCA1 indicates an 85% lifetime risk of developing breast cancer in women 3

1 American Cancer Society (2008)2 National Institute of Health (2008)3 Narod, Foulkes (2004)Image: Electron microscopy by cancer-alternative.net

BRCA1 in Ovarian Cancer• Ovarian cancer occurs in 1 out of 67 women 1

• It is a very deadly form of cancer, with a mortality rate of 55% after 5 years 1

• BRCA1 is mutated in 12% of women with invasive ovarian cancer 2

• A mutation in BRCA1 indicates a 40% lifetime risk of developing ovarian cancer 2

1 American Cancer Society (2008)2 Narod, Foulkes (2004)Image: Myriad Genetics

Discovery of the Gene

• BRCA1 was first cloned in 1994 by Myriad Genetics in Salt Lake City

• The technique used was positional cloning by genetic linkage analysis

• It was isolated to 17q21

Genetics Home Reference

The Gene

• RING-finger domain on the N-terminus

• involved in ubiquitination

• 2 nuclear localization motifs on exon 11

• BRCT domain on the C-terminus

• this is a conserved sequence for DNA repair and cell-cycle control

Narod, Foulkes (2004)

BRCA1 in the Organism:Caretaker of Genomic Stability

• Knockout mice

• BRCA1 -/- embryos die early in development (day 8 or 9)

• BRCA1 is a tumor suppressor gene

• Loss of heterozygosity is required for tumorigenesis

• Loss of BRCA1 promotes genomic instability

• Over-expression of BRCA1 leads to growth suppression

Image of the chimeric knockout mice being developed in P&S labs

in 1997

Molecular Roles of BRCA1:BRCA1 acts in many different cellular complexes with many

functions

• DNA repair

• Gene transcription regulation

• Cell cycle checkpoints

• Ubiquitination

BRCA1 ProteinProtein Data Base

Double Strand Break DNA Repair

•DSBs result from ionizing radiation

•Two Types of Repair:

•Non-homologous end-joining

•Homologous recombination

I couldn’t resist this image from Healthnet

Non-homologous End Joining

• Broken ends of the chromosome are brought together and rejoined by DNA ligase

• This is a very error-prone method

• Can lead to oncogenic chromosomal rearrangements

Smith, Smith, Mezard “Tying Up Lose Ends” (2001)

Homologous Recombination

• BRCA1, BRCA2, and RAD51 mediate HR repair

• Without BRCA1, the cell must rely on NHEJ

Zhang, Powell (2005)

Transcription Regulation

• BRCA1 involved in transcriptional machinery

• BRCA1 can act as a co-activator or co-repressor of transcription

• One of its specific genetic activation targets is p21

• recall this is a cyclin-dependent kinase inhibitor, important at the G1-S checkpoint

Mullin, Quinn, Harkin (2006)

Cell Cycle Checkpoints• BRCA1 regulates the cell cycle in

response to DNA damage

• For example, BRCA1 represses transcription of Cyclin B, which is needed for entry into mitosis

Noguhi (2006). Drexel University

Ubiquitination

• BRCA1 is an E3 ligase that exists as a heterodimer with BARD1

• RING finger domain binds to E2s

• BRCA1 ubiquitination has different effects on different substrates

• Recent reports show that ubiquitination is involved in BRCA1 recruitment to DNA damage sites

Buchwald, Stoop (2006)

Tissue Specific Model

• BRCA1 tumors resemble breast stem cells

• BRCA1 expression is necessary for breast stem cell differentiation

• Loss of BRCA1 results in genetically unstable breast stem cells

Liu (2008)

Articles Cited:

• Powell, Kachnic. Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity, and the cellular response to ionizing radiation. Oncogene. 2003.

• Narod, Foulkes. BRCA1 and BRCA2: 1994 and Beyond. Nature. 2004.

• Wu, Koike, et al. The ubiquitin E3 ligase activity of BRCA1 and its biological functions. Cell Division. 2008.

• Zhang, Powell. The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair. Molecular Cancer Research. (2005).

• Liu, et al. BRCA1 Regulates human mammary stem/progenitor cell fate. PNAS. 2008.

• Petrucelli, et al. BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer. Gene Reviews. 2007.

• Mullan, Harkin. The Role of BRCA1 in transcriptional regulation and cell cycle control. Oncogene. 2006.