Countless studies have proven a relationship between BRCA mutations and breast and ovarian cancers
. Unfortunately, major gaps still exist related to the mechanisms that modify the risk of cancer among patients with BRCA1/2 mutations.
The authors of new research published by Molecular Cell
discovered 3 genes in BRCA1/2- deficient cells that may add to the risk of cancer. Specifically, these genes fuel genome instability during DNA repair, which can lead to lesions and tumors.
“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. “We are currently conducting experiments to test this hypothesis.”
Normal BRCA1/2 genes are tumor suppressors and make sure that breast and ovarian cells grow normally. If the genes become mutated, cells can rapidly divide unchecked, which is a common precursor to cancer.
During cell replication, DNA double helixes unwind and separate. Each half of the DNA acts as a template for the creation of a new strand, according to the authors.
When the DNA strand separates, the halves form a replication fork. If the replicating DNA becomes stressed, BRCA genes prevent the forks from being degraded, thereby avoiding genomic instability, according to the study.
The authors discovered that the SMARCAL1, ZRANB3, and HLTF genes cause fork degradation in cells with mutated BRCA genes.
Deficiency in these 3 genes was observed to restore fork integrity and lowered genome instability in cells with mutated BRCA1/2, according to the study. This action suppresses DNA lesions that may increase the risk of cancer.
The authors also found that inhibiting SMARCAL1 in BRCA1-deficient breast cancer cells resulted in chemotherapy resistance, according to the study. Identifying a defense mechanism in breast cancer cells could inform the development of novel therapies for chemotherapy-resistant disease, the authors concluded.