By Janet Soper and its Effects in Breast Cancer and Ovarian Cancer

Breast Cancer 211,300 new cases of invasive breast cancer in women in ,200 deaths from breast cancer in 2003 Most frequently diagnosed non-skin cancer in women Second among cancer deaths in women

Genetically Predisposed 90% of hereditary breast cancers have a mutation in BRCA1 or BRCA2 5% of all breast cancers show a mutation in BRCA1 or BRCA2 b/humandevelopment/stage2/lectures /cancergenes/brca-1/brca-1.gif

Specifically, BRCA1 confers… Risk for ovarian cancer as well as breast cancer Earlier age of onset 80% lifetime risk of cancer- high penetrance Distinct tumors from BRCA2 mutations: invasive, high grade, lymphocyte infiltration s/plon/presentation_text.html

What is BRCA 1? Cloned in 1994 through genetic linkage to be on chromosome 17 Expressed in most proliferating cells mainimage.html whats_a_genome/Chp1_2_1.shtml

What does BRCA1 do? Multitude of roles have been proposed: – –DNA replication – –cell cycle checkpoint control – –DNA repair – –regulation of transcription – –protein ubiquitination – –apoptosis – –chromatin remodeling www- ermm.cbcu.cam.ac.uk/ h.htm

In knockout mice… …null for both BRCA1 and BRCA2, embryos died early in development showed high levels of cell cycle inhibitor p21 radiation sensitivity and measurable drop in rate of homologous recombination /journal/images/psjr_ gif

Just in the mammary glands When BRCA1 was knocked out in just the mammary glands of mice, tumors developed. When p53 was also mutated, there were even more tumors. Most tumors in breast and ovarian cancer(90%) have inactivated p53. apr99/niddk- 29.htm

Homologous Recombination Repair of a double strand DNA damage by breakage of two homologous DNA molecules and strand exchange e/Vol11/News-Scheme1.jpg

In Cancer Tumor suppressor gene One copy inherited, the second by LOH Heterozygosity is not enough to cause problems with DSB repair in mutations found thus far Why only in breast and ovarian cancer? – –These areas of proliferation naturally incur the most DNA damage so require the most homologous recombination – –Expression increases during pregnancy and lactation, increasing the risk

Mutations Primarily missense, nonsense, and splice-site mutations of single amino acids in one of its binding domains plon_026.gif

C-terminus Two BRCT motifs necessary for protein-protein binding Truncated by insertion or creation of a stop codon= cancer BACH1 has been associated with this domain gloverlab.biochem.ualberta.ca/ structures.html

BACH1 BRCA1-associated c-terminal helicase BRCA1 regulates the cellular location of BACH1 Over-expression of mutated BACH1 decreases DNA repair Over-expression of mutated BACH1 with an additional mutation in the BRCA1 binding domain rescues

N-terminus Ring finger domain for protein-protein interaction and E3- ubiquitin ligase activity Mutation=cancer and radiation sensitivity Ubiquitination must be important to DNA repair and BRCA1 function netics/9710gen.htm

BARD1 and BAP1 Binding to BARD1 (BRCA1-associated RING domain protein) increases the ubiquitination function of BRCA1 Also interacts with BAP1, a ubiquitin hydrolase en.htm

Ubiqui-WHAT?? So it can prevent or promote ubiquitin mediated protein degradation May ubiquintinate each other FANCD2 – –mono-ubiquitinated in response to DNA damage – –mutation in this leads to radiation sensitivity as well

How does this cause Cancer? Resembles p53, which is mutated in most cancers Makes DNA maintenance less secure, allowing more flaws which can be tumorigenic carper.senate.gov/ spotlight- breastcancer.html

Sources Brody, Lawrence C. and Biesecker, Barbara B. “Breast Cancer: The High-Risk Mutations”. Cancer Facts and Figures 2003, American Cancer Society Liu, Yilun and West, Stephen. (2001). “Distinct Functions of BRCA1 and BRCA2 in double strand break”. Powell, Simon N. and Kachnic, Lisa A. (2003). “Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation”. Oncogene, 22,