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

•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.

History of BRCA2

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

•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.

www.wellesley.edu/ cancer/adeno-p53.gif

P53 prevents proliferation if DNA is damaged.

Theory: BRCA2 mutations lead to other genes becoming mutant and tumor formation, ie. p21 or p53.

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.

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

Nature Reviews Molecular Cell Biology 4; 435-445 (2003); doi:10.1038/nrm1127

Homologous Recombination

•Homologous recombination

potential determined by irradiation

sensitivity and sensitivity

to mitomycin C.

•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.

Nature Reviews Molecular Cell Biology 4; 435-445 (2003); doi:10.1038/nrm1127

Found:

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

•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

•Not limited to breast cancerAlso linked to:

Male Breast Cancer

Ovarian

Prostatic

Pancreatico biliary

Gastric

Colon

Melanoma

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

BRCA2 as an indicator

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

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.

El Fin

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

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.

Treatment options

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

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

Nature Reviews Molecular Cell Biology 4; 435-445 (2003); doi:10.1038/nrm1127

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

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

mutant tumor suppressor caused cell cyle arrest due to truncated C terminal

Homologous recombination allows for DNA repair preventing genomic instability.