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BRCA1 The First Breast Cancer Gene Presentation By Liz Mosley.

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1 BRCA1 The First Breast Cancer Gene Presentation By Liz Mosley

2 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

3 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

4 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

5 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)

6 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

7 Molecular Roles of BRCA1: BRCA1 acts in many different cellular complexes with many functions DNA repair Gene transcription regulation Cell cycle checkpoints Ubiquitination BRCA1 Protein Protein Data Base

8 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

9 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)

10 Homologous Recombination BRCA1, BRCA2, and RAD51 mediate HR repair Without BRCA1, the cell must rely on NHEJ Zhang, Powell (2005)

11 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)

12 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

13 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)

14 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)

15 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.


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