Unraveling the molecular link between heavy metal exposure and triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that lacks targeted therapies. Individuals with Breast Cancer 1 (BRCA1) gene mutations have a significantly higher risk of developing TNBC in their lifetimes compared to the rest of the population. However, roughly eighty percent of TNBC cases cannot be explained by germline mutations. TNBC disproportionately affects populations that live in closer proximity to areas contaminated with heavy metals including cadmium (Cd). Cd is a heavy metal group 1 carcinogen that has a long biological half-life in the human body. Epidemiological studies demonstrate that Cd exposure increases breast cancer risk and in vitro studies determined that Cd exposure promotes TNBC initiation in normal human breast cells. Cd is known to displace zinc (Zn) from Zn coordinating proteins and several Zn coordinating proteins are important for DNA double-strand break (DSB) repair including RAD50 and BRCA1. Cd promotes higher levels of DSBs and sister chromatid exchanges indicative of DSB repair pathway inhibition. Whether Cd promotes TNBC initiation and progression by disruption of DSB signaling and repair, including direct inhibition of RAD50 or BRCA1, remains to be established. The experiments proposed to test the hypothesis that Cd exposure promotes TNBC initiation and progression by disruption of multilateral DSB signaling and repair will be conducted in two phases. During the mentored K99 phase, mass spectrometry, single-molecule imaging using isolated recombinant proteins and DNA curtain assays, and CRISPR-based editing will be employed to determine how Cd directly targets DSB repair proteins to disrupt DSB Repair pathway “choice”. While in the mentored phase, the candidate will take advantage of career development resources made available by the University of Louisville Center for Integrative Environmental Health Sciences and will apply research and career development skills to didactic lecturing, mentoring, writing, and presentation opportunities. In the non-mentored R00 phase of the project, technical skills gained from the K99 phase will be used for mechanistic studies to interrogate the role of Cd-induced fusion genes in TNBC development (Aim 2). These experiments will provide data needed for initial independent publications and preliminary data for R-series grants and will establish an independent direction for the candidate from her mentor. Modified