OESTROGEN-INDUCED DNA damage in BRCA1 mutation carriers may play a central role in cancer initiation, with new findings highlighting both environmental risks and a potential dietary protective strategy.
Oestrogen-Induced DNA Damage in BRCA1 Mutation Cells
Carriers of germline mutations in BRCA1 face a significantly increased lifetime risk of breast and ovarian malignancies, with cancer initiation linked to mutagenesis and loss of heterozygosity. Approximately 70% of BRCA1-associated breast cancers are triple negative, lacking progesterone, human epidermal growth factor receptor 2, and oestrogen receptors, and are thought to arise from oestrogen receptor and progesterone receptor negative luminal progenitor cells. However, mechanisms driving carcinogenesis in these cells have remained unclear.
Investigators analysing oestrogen receptor negative mammary cells demonstrated that oestrogen and its metabolites can directly impair DNA replication in heterozygous BRCA1 mutation cells. These compounds were shown to inhibit replication fork progression and induce DNA adduct formation, resulting in DNA breaks, large deletions, and cancer initiating mutations, including loss of heterozygosity.
Environmental Contributors to Genomic Instability
The study further identified environmental contributors to genomic instability. The widely used herbicide Atrazine was found to similarly disrupt replication fork progression and promote genomic instability in BRCA1 mutation cells. These findings suggest that both endogenous hormonal processes and external environmental exposures may converge to increase cancer risk in this population.
Importantly, these effects were observed in oestrogen receptor negative cells, which are typically unresponsive to hormone-based therapies, underscoring the complexity of tumour development in triple negative disease and the challenges associated with treatment.
Dietary Intervention Shows Protective Potential
To address the observed genotoxic effects, researchers evaluated several dietary compounds and identified Indole-3-carbinol as a promising candidate. This compound prevented replication stress and reduced genomic instability in BRCA1 mutation cells exposed to oestrogen.
These findings indicate that alterations in oestrogen metabolism, whether driven by internal or environmental factors, can promote DNA damage in susceptible cells. The data also suggest that dietary intervention may offer a preventative approach, with Indole-3 carbinol emerging as a potential therapeutic strategy for individuals carrying BRCA1 mutations.
Reference
Deshpande M et al. Endogenous and environmental factors that induce DNA replication defects and genomic instability in ER-negative heterozygous BRCA1 cells. Scientific Reports. 2026; https://doi.org/10.1038/s41598-026-46028-5.
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