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BRCA 1 Gene

BRCA 1 Gene. and its Effects in Breast Cancer and Ovarian Cancer. By Janet Soper. Breast Cancer. 211,300 new cases of invasive breast cancer in women in 2003 40,200 deaths from breast cancer in 2003 Most frequently diagnosed non-skin cancer in women Second among cancer deaths in women.

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BRCA 1 Gene

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  1. BRCA 1 Gene and its Effects in Breast Cancer and Ovarian Cancer By Janet Soper

  2. Breast Cancer • 211,300 new cases of invasive breast cancer in women in 2003 • 40,200 deaths from breast cancer in 2003 • Most frequently diagnosed non-skin cancer in women • Second among cancer deaths in women www.dressdownday.ca/

  3. 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 https://courses.stu.qmul.ac.uk/smd/kb/humandevelopment/stage2/lectures/cancergenes/brca-1/brca-1.gif

  4. 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 http://www.baylorcme.org/breastcancer/presentations/plon/presentation_text.html

  5. What is BRCA 1? • Cloned in 1994 through genetic linkage to be on chromosome 17 • Expressed in most proliferating cells http://www.genomenewsnetwork.org/whats_a_genome/Chp1_2_1.shtml www.bmm.icnet.uk/ mainimage.html

  6. 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/ 01003155h.htm

  7. 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 http://healthsciences.columbia.edu/news/journal/images/psjr_170108.gif

  8. 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. www.nih.gov/news/pr/ apr99/niddk-29.htm

  9. Homologous Recombination • Repair of a double strand DNA damage by breakage of two homologous DNA molecules and strand exchange http://www.onk.ns.ac.yu/Archive/Vol11/News-Scheme1.jpg

  10. 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

  11. Mutations • Primarily missense, nonsense, and splice-site mutations of single amino acids in one of its binding domains www.baylorcme.org/.../thumbnails/ plon_026.gif

  12. 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

  13. 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

  14. 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 http://www.hosppract.com/genetics/9710gen.htm

  15. BARD1 and BAP1 • Binding to BARD1 (BRCA1-associated RING domain protein) increases the ubiquitination function of BRCA1 • Also interacts with BAP1, a ubiquitin hydrolase http://www.hosppract.com/genetics/9710gen.htm

  16. 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

  17. http://www.the-scientist.com/images/yr2003/feb10/brca.gif

  18. 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

  19. Sources Brody, Lawrence C. and Biesecker, Barbara B. “Breast Cancer: The High-Risk Mutations”. http://www.hosppract.com/genetics/9710gen.htm Cancer Facts and Figures 2003, American Cancer Society Liu, Yilun and West, Stephen. (2001). “Distinct Functions of BRCA1 and BRCA2 in double strand break”.http://breastcancer.com/content/4/1/009 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, 57845791.

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