What is the role of BRCA in cancer development?

DNA damage and repair

• Mutations are alterations in the DNA that may change the structure, function and amount of certain proteins in cells, which may consequently contribute to cancer development.^1,2
• DNA damage can manifest, e.g., as single-strand breaks (SSBs) or as double-strand breaks (DSBs) in which either one or both DNA strands are damaged.^3,4
• In normal cells, a variety of DNA repair mechanisms maintain genomic stability, and DNA damage is repaired through distinct repair pathways.^1,5
  • SSBs are repaired by base excision repair (BER) and DSBs are repaired either by relatively accurate homologous recombination repair (HRR) or by non-homologous end-joining (NHEJ) which is not as accurate as HRR.^4,5
• Defective DNA repair contribute to accumulation of other mutations and genomic instability, such as oncogene activation or loss of tumor-suppressors, which may promote cancer development.^1,3,4

The role of BRCA mutations in tumor development and progression

• BRCA mutation is one of the key drivers of cancer pathology.⁶
• BRCA1 or BRCA2 (BRCA1/2) proteins are critical components for functional HRR and the repair of DSBs, the most lethal form of DNA damage.⁴
• If DSBs cannot be repaired, due to deleterious mutation in BRCA1/2 genes, mutations and genomic instability increase which may lead to the development of cancer.^1,4
• About 5% of the breast cancer patients harbor germline BRCA1/2 mutation, and BRCA1/2 mutation increases the lifetime risk of developing breast cancer from 5% of general female population to approximately 70%.^7-9

Defective BRCA as therapeutic target

Lack of functional BRCA1/2 and deficient HRR in tumors represent an opportunity for targeted therapy.⁴ Normal cells with a defective DNA repair mechanism depend on a compensatory repair pathway for survival. In HRR-deficient cancer cells, synthetic and cancer-specific lethality can be induced by targeting another functional DNA repair mechanism, such as BER. The cells with several defective repair pathways cannot fully repair the accumulating DNA damage, which may lead to cancer cell death.⁴

References

1. Lord CJ & Ashworth A. Nature. 2012 Jan 18;481(7381):287-94.
2. Prabantu VM, et al. Front Mol Biosci. 2021 Mar 10;7:620554.
3. Jackson SP & Bartek J. Nature. 2009;461(7267):1071-78.
4. O’Connor MJ. Mol Cell. 2015 Nov19;60(4):547-60.
5. Chatterjee N & Walker GC. Environ Mol Mutagen. 2017 Jun;58(5):235-263.
6. Balmaña J, et al., Ann Oncol. 2011;22(Suppl. 6):vi31-vi34.
7. De Talhouet S, et al. Sci Rep. 2020 Apr 27;10(1):7073.
8. Sung H, et al. CA Cancer J Clin. 2021 May;71(3):209-249.
9. Kuchenbaecker KB, et al. JAMA. 2017; 317:2402-2416.