The role of And-1 in R-loop and endocrine resistance in breast cancer

Project Summary As one type of endocrine therapy (ET) drugs, aromatase inhibitors (AIs) are the first line of treatment for ER+ breast cancer; however over 20% of patients eventually develop AI resistance during treatment. Changes in the estrogen receptor 1 (ESR1) gene, including mutations, are one of the major mechanisms contributing to AI resistance, for which there is currently no treatment. Thus, it is urgent to develop a novel approach to overcome AI resistance caused by ESR1 mutations. We recently identified an R-loop located at a transcriptional enhancer of ESR1 that regulates ESR1 expression, providing a novel approach to overcome AI resistance by targeting R- loop resolution. And-1 is an HMG box domain-containing protein involving in DNA replication and repair. And-1 is highly expressed in tumors but not in normal tissues, and is essential for tumor cell growth and proliferation. Multiple independent studies have identified And-1 as an excellent target gene for cancer therapy. Our preliminary studies indicated that And-1 is critical for R-loop resolution. Using both high-throughput and in silico drug screens, we successfully identified potent And-1 inhibitors. The major objectives of this application are to: (1) determine a novel molecular mechanism by which And-1 promotes R-loop resolution using in vitro and in vivo assays, and (2) assess the effects of And-1 inhibitors on AI resistance using AI resistant patient-derived xenograft (PDX) and syngeneic breast cancer models. The completion of proposed studies will not only elucidate a new mechanism regulating R-loop resolution in ER+ breast cancer, but also provide an innovative therapeutic strategy to treat AI-resistant breast cancer patients.