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

George Washington University, Washington DC

Investigators

Abstract

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.