Tumor Suppressor Gene Involved in Breast and Ovarian Cancers

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 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.

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