Tumor Suppressor Gene Involved in Breast and
Ovarian Cancers 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
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
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
The Discovery of BRCA1
Powell, SN. Roles of BRCA1 and BRCA2 in homologous recombination. Oncogene (2003) 22.
• Cloned in 1994 • Mapped to Chromosome 17q21• 1863 amino acids• C-terminus BRCT domain• N-terminus ring finger domain
BRCA1: A Not Completely Known Function
Narod, Steven A. BRCA1 and BRCA2: 1994 and Beyond. Nature Reviews (2004), 670.
BRCA1: DNA Repair
Kennedy, Richard D. The Role of BRCA1 in the Cellular Response to Chemotherapy. Journal of National Cancer Institute (2004), 1660.
www.nature.com/.../ n7/fig_tab/ni0703-624_F1.html
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.
BRCA1: Checkpoint Control
Kennedy, Richard D. The Role of BRCA1 in the Cellular Response to Chemotherapy. Journal of National Cancer Institute (2004), 1660.
Phosphorylation of BRCA1IF 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.
BRCA1: Ubiquitination
Kennedy, Richard D. The Role of BRCA1 in the Cellular Response to Chemotherapy. Journal of National Cancer Institute (2004), 1660.
The Ring-finger Domain
Narod, Steven A. BRCA1 and BRCA2: 1994 and Beyond. Nature Reviews (2004), 669.
• E3 Ubiquitin ligase• BARD1 binding enhances BRCA1 ubiquitin ligase activity
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
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
Hereditary vs. Sporadic
Kennedy, Richard D. The Role of BRCA1 in the Cellular Response to Chemotherapy. Journal of National Cancer Institute (2004), 1660.
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
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.
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
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
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