Wednesday, April 2, 2025
4/2/2025
Epigenetic dependencies and vulnerabilities in endocrine-resistant breast cancer - In this proposal we aim to identify epigenetic dependencies in breast cancer to enhance the survival rate of patients. We aim to investigate epigenetic vulnerabilities in endocrine-resistant breast cancer, specifically targeting the newly discovered CoREST-SWI/SNF axis. Around 80% of breast cancer cases are estrogen receptor positive (ER+). Existing treatments target the estrogen pathway, but approximately 40% of patients develop intrinsic resistance, leading to recurrence within 5 to 10 years. Furthermore, acquired antiestrogen resistance is common in the metastatic setting, contributing to patient mortality. Therefore, there is an urgent need to identify new therapeutic targets and mechanisms to combat metastatic endocrine-resistant ER+ breast cancer. Our study focuses on identifying epigenetic mechanisms mediated by a CoREST-SWI/SNF axis in two key resistant settings of endocrine resistance. We recently discovered that the CoREST complex, which includes the histone deacetylases HDAC1/2 and histone H4 lysine 4 demethylase LSD1, regulates breast cancer cell plasticity and endocrine therapy resistance, mediated by the loss of ESR1 expression (which encodes for ER). Additionally, we showed that CoREST interacts with the ATPase chromatin remodeling SWI/SNF complexes, and genetic and pharmacological inhibition of CoREST block tumorigenesis of endocrine resistant cells. Mechanistically, CoREST-SWI/SNF regulates the ER pathway in endocrine sensitive cells while regulating the AP-1 pathway in endocrine resistant cells upon loss of ER. Given our discovery of the functional crosstalk between ER pathway and CoREST and physical interaction between CoREST and SWI/SNF, here we propose two specific aims to dissect the CoREST-SWI/SNF axis endocrine resistant breast cancer mediated by acquired mutations in the estrogen pathway and SWI/SNF. In aim 1, we will determine the role of the CoREST-SWI/SNF axis in endocrine-resistant breast cancer with ESR1 mutations. We will study the role of CoREST in cell proliferation, its binding to chromatin in the presence of ESR1 mutations, and its physical and functional association with SWI/SNF both in cell lines and in xenografts and PDX models. We will also evaluate the effects of CoREST inhibition, alone or in combination with SWI/SNF inhibition on tumor burden. In aim 2, we will determine the role of CoREST in endocrine-resistant breast cancer with mutations in the SWI/SNF gene ARID1A. To this end, we will test whether CoREST inhibition renders ARID1A-deficient cells sensitive to fulvestrant, both in vitro and in vivo. Additionally, we will mechanisms of chromatin accessibility, gene regulation and tumor burden mediated by CoREST in cells lacking ARID1A. This proposal aims to improve the overall survival of patients with metastatic breast cancer by identifying novel therapeutic targets and mechanisms.
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