Replication Stress and DNA Damage Response Drives ESR1 Mutant Metastasis

Our research focus is estrogen receptor (ER)-positive luminal breast cancer, representing 75% of primary breast cancer patients, who are prescribed adjuvant endocrine therapy (ET) with hormonal agents. While recurrences are delayed by the use of ET, resistance can evolve with the development of metastatic breast cancer (MBC) in about one-fourth of ER-positive patients. MBC patients acquire ESR1 mutations in a significant percentage of cases. Our overall goal is to identify new therapeutic vulnerabilities in ESR1m preclinical models that can effectively block distant metastatic progression. Our proposal is highly translational. We hypothesize that acquired ESR1m function as activated “oncogenes” inducing defective replication stress (RS) that suppresses the DNA damage response (DDR), leading to a metastatic phenotype with actionable targets. Our innovation includes a unique transplantable ER+ patient derived xenograft (PDX) frozen metastatic tumor bank to explore the effects of selective cell cycle and DDR inhibitors. In Aim 1 we will study RS and DDR signaling in ex vivo metastatic organoid cultures, focusing on ATR/Chk1, and PARP inhibitor effects on the DDR and its interactions with ESR1m. In Aim 2, we will focus on cell cycle proteins AURKA/B and CDK1/2 to arrest the cell cycle in ESR1m tumors. In Aim 3 we will evaluate mutant metastasis in vivo and the effects of novel therapeutics on estrogen responses, EMT, and stem cell blockade. It is essential that the discovery of new therapeutic targets and the preclinical testing of novel approaches be performed using metastatic models. Currently most preclinical investigators only evaluate primary tumor proliferation, which may not reflect the ability of targeted inhibitors to block the complex steps of metastasis. We predict that identifying the heterogeneity of driver mechanisms using experimental modeling of ESR1 mutants will serve an important role in the development of therapeutic combination interventions to overcome the clinical problem of resistance and rapid tumor progression. Our project will fill a big gap in our clinical knowledge of how best to treat breast cancer patients who recur with multiple and heterogeneous ER-positive metastases. With successful completion of our Aims we can impact the effective ET maintenance of patients with ER-positive MBC and significantly delay time to progression.