1. BRCA1
Breast Cancer

2. BRCA1 has many binding domains and thus involved with several complexes with distinct functions
Two functional domains: N-terminus RING finger domain and the C-terminus BRCT domain
Steven A. Narod & William D. Foulkes, 2004

3. BRCA1 functions with multiple proteins
BRCA1 as a DNA damage protein
BRCA1 as a signal transducer; checkpoint activator
BRCA1 as a tumor suppressor
Kevin W. Caestecker, Gerlinde R. Van de Walle, 2012

4. BRCA1 as a DNA damage repair protein in homologous recombination
DNA activation:
DSB DNA damage  Mre11-RAD50-Nbs (MRN) bind to DSB ATM recruited by MRNATM phosphorylates H2AXBRCA1 recruited to foci and activated by phosphorylation via ATR/ATM
Lea M Starita, Jeffrey D Parvin, 2003

5. Homologous Recombination

6. BRCA1-/- in mice causes embryonic lethality; growth retardation, apoptosis, cell cycle defects, and genomic instability
A) Wild-type E3.5 blastocyst. (B) Outgrowth after three days of culture. The inner cell mass (ICM) is surrounded by trophoblast giant cells (TG). (C) Mutant E3.5 blastocyst. (D) Outgrowth after three days of culture. Only trophoblast giant cells have grown (no ICM growth). Bar, 20 μm in (A) and (C); 40 μm in (B) and (D).
Razqallah Hakem et al, 1996

7. 5-10% of total breast cancers have hereditary disposition
Can have up to 80% risk of being diagnosed with breast cancer during lifetime if have mutation (as opposed to 12%)

8. Tumor formation is result of additional mutations that promote growth advantage
Mutations occur in functioning copy of BR1
 BRCT domain
 missense mutations resulted in significant structural differences compared to wild-type and thus caused loss of tumor suppressor function
Deng CX 2002

9. BRCA1 mutations inherited autosomal dominant in pedigree

10. Targeted therapies target PARP enzyme
Joseph A. De Soto, Chu-Xia Deng 2006

11. Sources Steven A. Narod & William D. Foulkes, 2004
Kevin W. Caestecker, Gerlinde R. Van de Walle, 2012
Razqallah Hakem et al, 1996
Deng CX, 2002
Joseph A. De Soto, Chu-Xia Deng, 2006