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Mechanisms of epigenetic regulation of estrogen receptor function in breast cancer

乳腺癌雌激素受体功能的表观遗传调控机制

基本信息

批准号：
10622626
负责人：
Eneda Toska
金额：
$ 14.86万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-16 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10622626
关键词：
3-Dimensional AKT1 gene ARID1A gene Affect Androgen Receptor Androgens Architecture Automobile Driving Basic Science Binding Biochemical Breast Cancer Etiology Career Mobility Cells Cessation of life Chromatin Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy DNA Sequence Alteration Data Development Development Plans Drug resistance Elements Enhancers Epigenetic Process Estrogen Receptors Estrogen receptor positive Genetic Genetic Transcription Goals Growth Hormones Human In Vitro Knock-out Knowledge Laboratory Research Leadership Lysine Maintenance Malignant Neoplasms Malignant neoplasm of prostate Mammary Neoplasms Mediating Mediator Memorial Sloan-Kettering Cancer Center Mentors Metastatic breast cancer Methylation Methyltransferase Molecular Morphogenesis Mutation Nature Nuclear Hormone Receptors Nuclear Receptors Oncogenic Oncology Organoids PI3K/AKT PIK3CA gene PIK3CG gene Pathogenesis Pathway interactions Patient Care Patients Phosphorylation Play Positioning Attribute Post-Translational Protein Processing Principal Investigator Progression-Free Survivals Prostate Prostatic Neoplasms Regulation Reporting Research Resistance Resistance development Role Science Scientist Serine Signal Pathway Signal Transduction Therapeutic Translational Research Translations Treatment outcome United States Woman Work advanced prostate cancer breast tumorigenesis cancer diagnosis career career development collaborative environment design epigenetic regulation epigenomics genome-wide histone methyltransferase hormone therapy human disease improved in vivo in vivo Model inhibitor innovation interest malignant breast neoplasm mammary gland development men mouse model multimodality mutant novel therapeutics pharmacologic phase 3 study pre-clinical programs prostate cancer cell prostate cancer cell line prostate cancer model receptor function research clinical testing response skills tenure track therapy outcome treatment response tumor tumor growth tumorigenesis

项目摘要

PROJECT SUMMARY/ ABSTRACT CANDIDATE: My ultimate goal is to become a principal investigator focused on the epigenetic mechanisms driving the pathogenesis of human diseases. I seek to attain a tenure-track position allowing me to establish a research program that studies the epigenetic mechanisms driving breast cancer and the translation of basic research findings into potential new therapies. To achieve my goal, I have developed a career development plan with four key elements: 1) To expand and strengthen my experimental skills and scientific knowledge, 2) To enhance my leadership, mentoring skills, and professional development, 3) To receive support on my career transition from Dr. Ross Levine and research guidance and career support from my collaborators Drs. Maurizio Scaltriti, Sarat Chanderlapaty, Minkui Luo, and Charles Sawyers, Ari Melnick and my advisers Drs. Larry Norton and Ronglai Shen 4) To transition into a tenure-track research independent position. ENVIRONMENT: The proposed study will be conducted at MSKCC, acknowledged for its exceptional patient care, state-of-the-art facilities, and innovative research. I am part of the Human Oncology and Pathogenesis Program (HOPP) that brings together scientists with an interest in mechanism-based laboratory and translational research. Under the leadership of Dr. Charles Sawyers, HOPP creates a highly collaborative environment that will greatly facilitate my translational research efforts. RESEARCH: Alterations in the PI3K pathway occur in 40-60% of ER+ breast cancer or AR+ breast cancer, representing the most common genomic alteration in such tumors, and indicating that the PI3K signaling pathway plays an important role in the tumorigenesis of hormone-dependent tumors. There is important bidirectional regulatory crosstalk between PI3K and ER or AR signaling in breast and prostate cancers respectively, leading to tumors that adapt and survive when either single pathway is pharmacologically inhibited. I have recently demonstrated that PI3K inhibition activates ER function to drive tumor growth in ER+/PIK3CA mutants, through the epigenetic regulator KMT2D. We hypothesized that KMT2D could be a general mechanism in controlling nuclear hormone receptor function and regulate the AR-PI3K crosstalk at cell-specific enhancers of prostate cells. Preliminary data show that KMT2D is required for androgen response upon PI3K inhibition. We now aim to study the molecular mechanisms of KMT2D in the regulation of AR-PI3K crosstalk using prostate cancer cell lines and human prostate organoids (AIM 1 and 2). Furthermore, while searching for epigenetic regulators and their involvement in therapeutic response in ER+ breast cancer, we have also conducted a CRISPR knockout screen that identified the epigenetic regulator ARID1A as the top candidate whose loss mediates resistance to anti-ER therapy through lineage switching. To this end, we aim to dissect the in vivo function and the chromatin- based regulation of ARID1A as a key mediator of response to endocrine therapy (AIM 3). Altogether, this understanding is critical to design new and improved therapies for hormone-dependent tumors.

项目摘要/摘要