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Breast Cancer and BRCA2

Breast Cancer and BRCA2. 1 million women worldwide diagnosed. 1 out of 12 women in Western Europe and the United States 30% mortality rate Highest cause of death among women 50 to 55 years of age. http://www.dkfz-heidelberg.de/tumour_genetics/breast.htm. History of BRCA2.

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Breast Cancer and BRCA2

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  1. Breast Cancer and BRCA2

  2. 1 million women worldwide diagnosed. • 1 out of 12 women in Western Europe and the United States • 30% mortality rate • Highest cause of death among women 50 to 55 years of age. http://www.dkfz-heidelberg.de/tumour_genetics/breast.htm

  3. History of BRCA2 • Wooster located the BRCA2 from gene linkage studies of 15 breast cancer predisposed families in 1994. • Hakannsson and Serova sequenced the 10,443 nucleotide gene in 1995.

  4. Simon N Powell,1 and Lisa A Kachnic2 Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA; 2Department of Radiation Oncology, Boston Medical Center, Boston, MA, USA

  5. Knockout mice in embryogenesis with homozygous loss of function in Brca2 had high expression of p21, small growth, and die early in development. • Also seen to be sensitive to radiation. These together implicate possible role in DNA repair.

  6. P53 prevents proliferation if DNA is damaged. Theory: BRCA2 mutations lead to other genes becoming mutant and tumor formation, ie. p21 or p53. www.wellesley.edu/ cancer/adeno-p53.gif

  7. Association of BRCA2 with P53 • In clinical setting there is a high incidence of inactivation of P53, perhaps greater than 90%. • Further proof: P53 inactivation partially rescued developmental arrest in null BRCA2 mice. • Conclusion: BRCA2 mutations lead to other genes becoming mutant and tumor formation ie. p21 or p53.

  8. Overall: • Genomic instability results in tumor formation due to translocations, inversions, etc.

  9. Nature Reviews Molecular Cell Biology4; 435-445 (2003); doi:10.1038/nrm1127

  10. Homologous Recombination

  11. Homologous recombination • potential determined by irradiation • sensitivity and sensitivity • to mitomycin C.

  12. Mitomycin C creates crosslinks that requires homologous recombination to fix. • In Brca mutants, there was an increased sensitivity to Mitomycin C due to loss of ability to homologous recombination. Implicates BRCA genes in recombination role.

  13. Nature Reviews Molecular Cell Biology4; 435-445 (2003); doi:10.1038/nrm1127

  14. Found: • Maybe it turns Rad51 on in pathway. Expressing binding region to rad51 results in loss of homologous recombination and increased sensitivity to radiation.

  15. BRCA2 binds to ssDNA and helps RAD51 filament to form. • This RAD51 filament brings strand of DNA in for homologous recombination. Simon N Powell,1 and Lisa A Kachnic2 Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA; 2Department of Radiation Oncology, Boston Medical Center, Boston, MA, USA

  16. Not limited to breast cancer Also linked to: Male Breast Cancer Ovarian Prostatic Pancreatico biliary Gastric Colon Melanoma

  17. BRCA2 as an indicator http://www.dkfz-heidelberg.de/tumour_genetics/breast.htm

  18. http://www.dkfz-heidelberg.de/tumour_genetics/breast.htm

  19. Treatment Today: Lumpectomy: removal of tumor lump. Partial to total mastectomy: Tumor or breast cut, chest muscle left intact. Radical Mastectomy: Chest muscle removed along with lymph nodes under arms. All followed with either radiation and/or chemotherapy. Tamoxifen: acts against estrogen’s effects and suppresses growth of tumor. In clinical trials for effectiveness. Shows increased survival rate.

  20. El Fin

  21. http://www.erudit.org/revue/ms/2002/v18/n11/000456ar.html

  22. Tumor suppressor paradox: Sporadic: +/+  +/-  -/- all in one cell? Unlikely So should be a dominant acting form of BRCA mutation that keeps rest of w.t. protein from working in sporadic cases. Haven’t found it. Theory: BRCA2 mutations lead to other genes becoming mutant and tumor formation, ie. p21 or p53.

  23. Treatment options

  24. Overall: • Brca2 binds to Rad51 • Rad51 brings strand of DNA • in for homologous recombination • Homologous recombination allows for • DNA repair • DNA repair prevents genomic instability

  25. Simon N Powell,1 and Lisa A Kachnic2 Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA; 2Department of Radiation Oncology, Boston Medical Center, Boston, MA, USA

  26. Nature Reviews Molecular Cell Biology4; 435-445 (2003); doi:10.1038/nrm1127

  27. Simon N Powell,1 and Lisa A Kachnic2 Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA; 2Department of Radiation Oncology, Boston Medical Center, Boston, MA, USA

  28. Also found inactivation of p53 partially rescued the developmental arrest in Brca2 mice. Further proof of its role in DNA repair.

  29. mutant tumor suppressor caused cell cyle arrest due to truncated C terminal Homologous recombination allows for DNA repair preventing genomic instability.

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