Modeling the dynamics of BRCA1 promoter methylation relevant to triple-negative breast cancer
In: Student Reports, Summer 2023, The Jackson Laboratory
Pooka Kumar, Ph.D.
BRCA1 is a medically important tumor suppressor gene that normally protects the body from accumulating mutations as a result of DNA damage. Loss of BRCA1 function drives up to 40% of triple-negative breast cancers, which comprise the deadliest and most aggressive form of the disease. A rare BRCA1 promoter mutation c.-107A>T induces mosaic monoallelic BRCA1 promoter methylation in all tissue types and results in incident breast, ovarian, and colon cancers via the silencing of BRCA1. The dynamics of this gain of BRCA1 promoter methylation are not well understood. To deconvolute this process, we introduced this c.- 107A>T mutation in two in vitro cell lines and analyzed them for their methylation status at 30, 60, and 100 days in culture. We showed that the introduction of the c.-107A>T mutation caused initiation and progression of BRCA1 promoter methylation in the WIBJ2 induced pluripotent stem cell line, in cis with the c.-107A>T mutation. However, we found that, mysteriously, neither of these BRCA1 promoter methylation events occurred in the HEK293T cells. This work serves as an important step in furthering the scientific community’s understanding of developmental gain of methylation at the BRCA1 promoter in the presence of, and irrespective of, the c.-107A>T mutation.
Woodruff, Anthony, "Modeling the dynamics of BRCA1 promoter methylation relevant to triple-negative breast cancer" (2023). Summer and Academic Year Student Reports. 2740.