1. BRCA1: Tumor Suppression and Breast Cancer A breast cancer cell dividing. http://www.biologyreference.com/Co-Dn/Cytokinesis.html

2. 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.

3. Pathology of breast cancer in women carrying mutations in BRCA1 and BRCA2 Taken from the Breast Cancer Linkage Consortium (1997)

4. 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.

5. http://www.sciencedaily.com/videos/health_medicine/br east_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)

6. 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

7. Protein Structure Source - Breast cancer genetics: What we know and what we need May 2001,vol 7,no.5 pp-552-556.(Nature)Nature C-terminal BRCT domain Internal SQ Cluster domain N-terminal “ring finger” domain

8. 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

9. Other functions of BRCA1: Mediate Cell Cycle Checkpoints at S and G2/M Ubiquitination Apoptosis Regulation of DNA Replication

10. 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.

11. 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.

12. Clinical Applications CisplatinCisplatin CisplatinCisplatin 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.orgwww.wikipedia.org “Cisplatin”, “Resveratrol” Resveratrol

13. Sources 1.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.www.wikipedia.org 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. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=113705