Abstract
Breast cancer is the most common malignancy among women worldwide, with approximately 2.3 million women diagnosed and 685,000 deaths reported in 2020. It is a genetically and clinically heterogeneous disease comprising multiple subtypes that influence prognosis and treatment strategies. Hereditary breast cancer is most frequently associated with pathogenic variants in BRCA1, which confer up to a 72% lifetime risk of developing breast cancer, indicating an important need for a preventative treatment. A recent genome-wide association study investigating copy number variants identified a deletion in SULT1A1 may exert a protective effect in women carrying a BRCA1 pathogenic variant. Supporting in vitro data suggested that reduced SULT1A1 activity may contribute to this preventative association. Consequently, inhibition of SULT1A1 has been proposed as a potential preventative strategy in BRCA1-associated breast cancer. In the present study, the effects of ethinylestradiol, curcumin and quercetin on SULT1A1 activity were assessed in vitro. Curcumin and quercetin inhibited SULT1A1 activity across a range of concentrations, whereas ethinylestradiol showed no inhibitory effect. Based on these findings, curcumin and quercetin were further evaluated for their impact on cellular proliferation at concentrations shown to inhibit SULT1A1. However, no significant effects on proliferation were observed across multiple time points. The anti-cancer compound 2-methoxyestradiol, which is hypothesised to accumulate following SULT1A1 inhibition, significantly reduced cellular proliferation, consistent with previous literature. Notably, cell lines overexpressing SULT1A1 demonstrated improved survival at certain concentrations, suggesting that SULT1A1 expression may modulate the anti-cancer efficacy of this compound. DNA damage was evaluated as a marker of oncogenic potential in BRCA1-modified cells. Quercetin treatment increased DNA damage in BRCA1-modified cells compared with wild-type controls. Similarly, siRNA-mediated knockdown of SULT1A1 initially increased DNA damage in BRCA1-modified cells, although this effect was not sustained over extended periods. Overall, these findings do not provide strong support for SULT1A1 inhibition as a clinically translatable preventative strategy in BRCA1-associated breast cancer. Future studies should focus on directly assessing 2-methoxyestradiol accumulation following SULT1A1 inhibition and investigating additional markers of cancer-related phenotypes in different cellular models to further confirm the clinical applicability of SULT1A1 inhibition in BRCA1-associated breast cancer.