New Insights into How BRCA1/2 Mutations Cause Breast/Ovarian Cancer

Study highlights potential new therapeutic targets for BRCA1/2 mutation carriers

While it is well established that mutations in the BRCA1 or BRCA2 genes can lead to breast or ovarian cancer, researchers are just beginning to decipher the mechanisms that control this process. In a new study, scientists at Columbia University’s Herbert Irving Comprehensive Cancer Center (HICCC) have identified three genes in BRCA1/2-deficient cells that fuel genome instability during a critical DNA repair process, causing lesions that can lead to tumor formation.

“Our studies raise the possibility that inhibition of these genes could reduce the occurrence of breast and ovarian cancer in BRCA1/2 mutation carriers”, said study leader Alberto Ciccia, PhD, assistant professor of genetics and development at HICCC. “We are currently conducting experiments to test this hypothesis”.

BRCA1/2 – so-called tumor-suppressor genes – help ensure that breast and ovarian cells grow and divide at a normal pace. If these genes become mutated, cells are likely to reproduce uncontrollably, a common prelude to cancer.

When a cell replicates, DNA double helixes must unwind and separate, which each half serving as a template for the synthesis of a new double strand. As the strands begin to separate, the two halves, or prongs, form what is called a replication fork. If the replicating DNA is stressed, BRCA1/2 help prevent the forks from being degraded, thus avoiding genomic instability.

Dr. Ciccia and his colleagues discovered that three newly characterized genes – SMARCAL1, ZRANB3, and HLTF – cause the degradation of forks in cells with mutated BRCA1/2. Depletion of these factors restores fork integrity and reduces genome instability in BRCA1/2-deficient cells, thus suppressing potentially damaging DNA lesions that could favor cancer development.

The HICCC team also showed that inhibition of SMARCAL1 in BRCA1-deficient breast cancer cells caused resistance to chemotherapy, identifying a new chemoresistance mechanism in this form of breast cancer.

Study details:
“Restoration of Replication Fork Stability in BRCA1- and BRCA2-Deficient Cells by Inactivation of SNF2-Family Fork Remodelers.” Molecular Cell, Volume 68, Issue 2, p414–430.e8, 19 October 2017