Investigating Loss of Methylation at the BRCA1 Promoter as a Mechanism of Chemoresistance

Document Type


Publication Date

Summer 2022



JAX Location

In: Student Reports, Summer 2022, The Jackson Laboratory


Triple-Negative Breast Cancer (TNBC) is the deadliest form of breast cancer due to its aggressive nature and lack of clear treatment options. Around half of all TNBCs have a defective homologous recombination pathway (HR Deficient/HRD), mostly through loss of BRCA1 activity. Inactivation of BRCA1 can take place through promoter hypermethylation (BRCA1meth) or an inactivating mutation (BRCA1mut). Despite having identical genomic scars, BRCA1meth patients have worse outcome compared to BRCA1mut patients. Studies in the Liu Lab deconvoluted these dynamics, using patient derived xenograft (PDX) models to show BRCA1 promoter methylation to be dynamic. A loss in methylation at the BRCA1 promoter occurs after one cycle of cisplatin. This restores BRCA1 expression and renders the cancer cells resistant to cisplatin treatment. Here, I aim to further explore this adaptive chemoresistance in BRCA1meth TNBC. I found that after cisplatin treatment, methylation is robustly and consistently lost only at the BRCA1 promoter. Additionally, I identified six transcription factor (TF) candidates that may play a role in the local demethylation at the BRCA1 promoter, and I started to verify these candidates by starting a chromatin immunoprecipitation (ChIP) procedure.

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