BRCA1: Tumor Suppression and Breast Cancer

A breast cancer cell dividing.http://www.biologyreference.com/Co-Dn/Cytokinesis.html

BRCA 1 Overview• Tumor suppressor largely expressed in mammary

epithelial cells.

• Inheritance pattern similar to Rb.

• Mutated in ≈ 10% of breast/ovarian cancers.

• BRCA1 (+/-) women have lifetime risk of breast cancer ≈ 80%.

• BRCA1 cancers: high-grade, infiltrative tumors, usually aneuploid and estrogen receptor negative.

• Main function of wt BRCA 1 is DNA Repair.

Pathology of breast cancer in women carrying mutations in BRCA1 and BRCA2

Taken from the Breast Cancer Linkage Consortium (1997)

Genetics• Cloned in 1994

• Mapped to 17q21.

• Analogs in mouse, E. coli.

• Follows Knudson two-hit model: LOF of 2nd BRCA1 allele is required for cancer.

• However, BRCA1 homozygous mutants are not found in sporadic breast cancers.

http://www.sciencedaily.com/videos/health_medicine/breast_cancer/

Genetics

Ways to inactivate BRCA1:

1. Mutation – a number of single AA substitutions are known, most of which lead to protein truncation. (common)

2. Deletion of BRCA portion of Chromosome 17. (common)

3. Epigenetic silencing – methylation of certain BRCA1 residues (10% of the time)

BRCA1 gene copy number and protein expression analysis on breast tumor section. Tumor cells in a BRCA1 methylated sample are seen to have reduced BRCA1 gene copy numbers (red signal) compared with centromere 17 (green signal) by FISH.

Birgisdottir et al., Breast Cancer Research 2006, 8:R38

Protein Structure

Source - Breast cancer genetics: What we know and what we need May 2001,vol 7,no.5 pp-552-556.(Nature)

C-terminal BRCT domain

Internal SQ Cluster domain

N-terminal “ring finger” domain

Functions of BRCA1:Double-Stranded DNA Break Repair

Homologous Recombination

http://www.spring8.or.jp/en/current_result/press_release/2004/040507_fig/fig2

BRCA1 structure facilitates binding of 4 DNA strands.

When subjected to ionizing radiation or oxidative stress, BRCA1(-/-) cells cannot mediate the DS breakage and/or cross-linking that occurs.

BRCA1 is required for 3’ -OH invasion of template (red) strand

Other functions of BRCA1:

Mediate Cell Cycle Checkpoints at S and G2/M

Ubiquitination

Apoptosis

Regulation of DNA Replication

BRCA 1 Protein Function

BRCA1 null mouse embryos die early in development.

Total loss of BRCA1 also triggers p53-dependent growth arrest. Because of BRCA1’s role in DNA repair, p53 normally senses its loss and halts proliferation.

In BRCA1 (-/-) embryos, subsequent p53 inactivation allowed them to proceed in development.

BRCA 1 Protein Function

BRCA1 (-/-) adult mice developed mammary tumors with frequent p53 mutations.

In 90% of human breast cancers where BRCA1 has been inactivated, p53 has been inactivated as well.

Clinical Applications

                    

                    

Cisplatin

                    

                    

Cisplatin

Many BRCA1 carriers opt to undergo prophylactic bilateral mastectomy and/or hysterectomy.

Cisplatin, a chemotherapeutic agent, targets BRCA1 deficient cells by causing DNA crosslinking

Resveratrol, a phytochemical found in berries, has anti-cancer properties that likely involve the BRCA1/p53 apoptotic pathway.

Cisplatin

www.wikipedia.org “Cisplatin”, “Resveratrol”

Resveratrol

Sources1. Powell, Simon N. and Kachnic, Lisa A. Roles of BRCA1 and

BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation. Oncogene. Issue 22, 2003. 5784-5791.

2. “Cisplatin.” www.wikipedia.org. Microsoft Internet Explorer, accessed 25 February 2007.

3. Birgisdottir, V. et al. Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Research. Issue 8, 17 July 2006.

4. Gowen LC et al. BRCA1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nature Genetics. Issue 12, February 1996, 191-194.

5. Holland, Frei et al. “Breast-Ovarian Cancer Syndrome.” Cancer Medicine. London: BC Decker Inc. 2003.

6. “BRCA1 – ID# 113705.” Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=113705. Microsoft Internet Explorer, accessed 23 February 2007.