m6A Epitranscriptomic Drivers of Endocrine-Resistant Breast Cancer
Abstract
Rationale for Proposed Research: This project specifically addresses why some breast cancer patients develop acquired endocrine-resistant, recurrent, metastatic cancer. The current standard adjuvant treatment for patients with estrogen receptor a positive (ER+) breast cancer depends on menopausal status with aromatase inhibitors for post-menopausal and tamoxifen for pre-menopausal women. While these endocrine therapies have greatly increased the survival rate of patients with ER+ breast cancer, unfortunately, a major limitation is the development of acquired resistance in ~40% of initially responsive patients. The goal of our study is to understand how changes in chemical decorations or modifications added onto transcribed RNA, specifically adenosine methylation (m6A), and their downstream consequences affect the evolution of breast tumors from endocrine-sensitive to endocrine resistance and metastatic disease. Ultimately, these RNA chemical modifications change the expression of multiple proteins that regulate biological activities in a process termed epitranscriptomics. We have recently demonstrated that a cellular reader of these marks, HNRNPA2B1, is required to drive endocrine-resistant ER+ BC and that it alters a specific metabolic pathway that we have also shown influences tamoxifen efficacy. We now intend to globally assess these RNA marks dynamically impacts pathways of endocrine resistance, metastasis, cellular metabolism between endocrine-sensitive and -resistant ER+ BC. Our objectives will be achieved by completion of two distinct aims that will (1) use state-of-the-art genetic sequencing, proteomics, and bioinformatic technologies to definitively characterize RNA modifications and subsequent protein changes that influence endocrine sensitivity, and (2) determine relevance of epitranscriptomic control of serine metabolism in acquired resistance using advanced metabolomics tracing approaches. These studies will be performed in complementary relevant models of ER+ BC that have defined endocrine sensitivity or resistance, including established breast cancer cell lines and patient-derived ER+ BC tissues (PDX). We will also employ a pharmaceutical inhibitor of the enzyme that generates the m6A marks in RNA to determine if diminished m6A deposition is clinically relevant against BC cell and PDX tumor growth and whether it is a potential avenue for altering endocrine resistance. The resulting data will be the first direct identification of the requirement for changes in the epitranscriptome that regulates endocrine resistance and ER+ BC progression and will also address the overarching challenge to identify why some breast cancers become metastatic. Ultimate Applicability for Proposed Research: Prior studies have attempted to elucidate mechanisms that drive endocrine therapy resistance, yet the majority of these have focused on selective protein changes. Here we take a novel, global approach in describing the significance of the m6A epitranscriptome in ER+ BC progression. Further, this work will provide proof of principle that epitranscriptomic control of key pathways established to contribute to endocrine resistance and the serine synthetic metabolic pathway that is also necessary to promote endocrine resistance. This study will validate the relevance of RNA modifications in regulating biochemical pathways that promote recurrent disease, which occurs all too often after initially successful hormonal therapy. While these studies will interrogate the basic biological understanding of these mechanisms in ER+ BC, these findings have the potential for near-future clinical translation. Notably, inhibitors of RNA epitranscriptome modifiers are currently under development. Defining specific changes in RNA modifications that drive cellular activities that are necessary for ER+ BC progression will provide novel selective targets as a therapeutic strategy against endocrine-resistant metastatic disease, which ultimately is
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310018
Entities
People
- Brian Clem
Organizations
- United States Army
- University of Louisville