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Tumor Suppressor Gene Involved in Breast and Ovarian Cancers

Tumor Suppressor Gene Involved in Breast and Ovarian Cancers. BRCA1. www.ncbi.nlm.nih.gov/ SCIENCE96/gene.cgi?BRCA1. Summary. Facts about Breast and Ovarian Cancer Discovery of BRCA1 (cloning the gene) Normal Function Biological Role (Knockout experiment) BRCA1 and Cancer.

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Tumor Suppressor Gene Involved in Breast and Ovarian Cancers

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  1. Tumor Suppressor Gene Involved in Breast and Ovarian Cancers BRCA1 www.ncbi.nlm.nih.gov/ SCIENCE96/gene.cgi?BRCA1

  2. Summary • Facts about Breast and Ovarian Cancer • Discovery of BRCA1 (cloning the gene) • Normal Function • Biological Role (Knockout experiment) • BRCA1 and Cancer

  3. Breast and Ovarian Cancers • Breast cancer is 2nd leading cause of cancer death in women • Lifetime risk for ovarian cancer: 1/70 www.cancer.gov

  4. Familial Risk Factors • BRCA1 or BRCA2 carriers have a mean age of breast cancer diagnosis of 40 • BRCA1 mutation leads to 82% risk of breast cancer and 54% risk of ovarian cancer

  5. The Discovery of BRCA1 • Cloned in 1994 • Mapped to Chromosome 17q21 • 1863 amino acids • C-terminus BRCT domain • N-terminus ring finger domain Powell, SN. Roles of BRCA1 and BRCA2 in homologous recombination. Oncogene (2003) 22.

  6. BRCA1: A Not Completely Known Function Narod, Steven A. BRCA1 and BRCA2: 1994 and Beyond. Nature Reviews (2004), 670.

  7. BRCA1: DNA Repair Kennedy, Richard D. The Role of BRCA1 in the Cellular Response to Chemotherapy. Journal of National Cancer Institute (2004), 1660.

  8. Homologous Recombination vs. Non-homologous End Joining Miki, Yoshido. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA Damage. Cancer Science (2004), 868. www.nature.com/.../ n7/fig_tab/ni0703-624_F1.html

  9. BRCA1: Checkpoint Control Kennedy, Richard D. The Role of BRCA1 in the Cellular Response to Chemotherapy. Journal of National Cancer Institute (2004), 1660.

  10. Phosphorylation of BRCA1 IF DNA DAMAGE: • ATM phosphorylates BRCA1 to halt G2-M transition • BRCA1 phosphorylation activates p21 and blocks S-phase entry Miki, Yoshido. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA Damage. Cancer Science (2004), 869.

  11. BRCA1: Ubiquitination Kennedy, Richard D. The Role of BRCA1 in the Cellular Response to Chemotherapy. Journal of National Cancer Institute (2004), 1660.

  12. The Ring-finger Domain • E3 Ubiquitin ligase • BARD1 binding enhances BRCA1 ubiquitin ligase activity Narod, Steven A. BRCA1 and BRCA2: 1994 and Beyond. Nature Reviews (2004), 669.

  13. Knockout Mice: BRCA1 function • Exp 1: • Homozygous Brca1null embryos die ~day 6.5 due to cell-cycle block and increased p21 • 25% of BRCA1 heterozygotes develop tumors lsd.ornl.gov/mgd/phenotype/ ELS-Chr7-Foxa2-6.htm

  14. Knockout Mice: BRCA1 function • Exp 1: • Homozygous Brcanull embryos die ~day 6.5 due to cell-cycle block and increased p21 • 25% of BRCA1 heterozygotes develop tumors • Exp 2: • Brcanull/null/Tp53-/- • No p53, embryos die 9.5-10.5 days lsd.ornl.gov/mgd/phenotype/ ELS-Chr7-Foxa2-6.htm

  15. Hereditary vs. Sporadic Kennedy, Richard D. The Role of BRCA1 in the Cellular Response to Chemotherapy. Journal of National Cancer Institute (2004), 1660.

  16. Loss-of-function of BRCA1 and Cancer: DNA Repair • NO BRCA1: • Radiation sensitive, homologous recombination decreases 5 times. • Double stranded breaks corrected by non-homologous end joining. • Thus damaged DNA replicated. www.nature.com/.../ n7/fig_tab/ni0703-624_F1.html

  17. Loss-of-function of BRCA1 and Cancer: Checkpoint Control • If loss of BRCA1: • Defective G2/M checkpoint • p21 promoter failed to be activated • No S-phase stop if damaged DNA • p53 involvement increased Miki, Yoshido. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA Damage. Cancer Science (2004), 869.

  18. Loss-of-function of BRCA1 and Cancer: Ubiquination • If loss of BRCA1: • Ubiquination cannot occur • No protein degradation in response to stress • Increased DNA damage

  19. Key Points to Remember • Tumor Suppressor Gene • Proposed mechanisms in: • DNA repair • Cell-cycle control • Some involvement in ubiquination • Much of BRCA1 function is still unknown

  20. Sources • Kennedy, Richard D. The Role of BRCA1 in the Cellular Response to Chemotherapy. Journal of National Cancer Institute (2004), 1659-1668. • Lacroix, Marc. The “Portrait” of Hereditary Breast Cancer. Breast Cancer Research and Treatment (2005) 89: 297-304. • Miki, Yoshido. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA Damage. Cancer Science (2004), 866-871. • Narod, Steven A. BRCA1 and BRCA2: 1994 and Beyond. Nature Reviews (2004), 665-676. • http:ghr.nlm.nih.gov • www.cancer.gov

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