Abstract
Breast cancer is the most prevalent form of cancer globally, with an estimated 2.3 million new cases and 685,000 deaths globally in 2020. It is estimated that genetic predisposition is responsible for 5-10% of all breast cancers. Women carrying a germline pathogenic (disease-causing) variant in BRCA1 have an estimated cumulative lifetime risk of developing breast cancer of 72%.
Preventative therapy for women who are genetically predisposed to developing breast cancer is critical for improving clinical management and reducing the overall burden of cancer. Presently, the most effective risk reduction strategy is a bilateral mastectomy, where lifetime risk of breast cancer can be reduced from ~65% to <10%. However, this is an invasive and irreversible procedure, that can be significantly distressing especially to younger women, limiting its uptake. Recent research findings led to the discovery of a potential therapeutic target for reducing the risk of inherited BRCA1breast cancer. A genome-wide copy number variant (CNV) analysis of BRCA1 and BRCA2 pathogenic variant carriers, revealed that deletions overlapping SULT1A1 were associated with reduced breast cancer risk in BRCA1 pathogenic variant carriers. SULT1A1 is important for metabolism, bioactivation and steroid hormones and is widely expressed around the body. Ethinylestradiol (EE2) is a synthetic oestrogen known to inhibit SULT1A1.
This project aimed to assess differential gene expression in breast tumours with a SULT1A1 deletion and evaluate the impact of EE2 on breast cells with a loss of function BRCA1 variant (MCF-7BRCA1-/+), compared with breast cells with wild type BRCA1 (MCF-7). Gene expression analysis of breast tumour with a SULT1A1 deletion compared to breast tumour with diploid SULT1A1 expression revealed genes involved in the oestrogen response pathway and cell cycle checkpoints were differentially expressed. However, results showed that there was no difference in proliferation between MCF-7 and MCF-7BRCA1-/+ when treated with different EE2 concentrations (1-200nM). Lastly, to investigate SULT1A1 inhibition on DNA damage repair, a function of BRCA1, a 53BP1 immunocytochemistry protocol was optimised. Gene expression analysis revealed molecular differences between SULT1A1 deletion and diploid states in breast tumours, suggesting a protective effect from a SULT1A1 deletion. The absence of an effect of EE2 on cell proliferation, and consequently SULT1A1 inhibition suggested it has limited potential as a preventive treatment. However, since SULT1A1 activity was not directly assessed, other SULT1A1 inhibitors may possibly better replicate the protective effects seen in epidemiological studies.