权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

the mTOR translational control pathway in tamoxifen resistant ER+ breast cancer

他莫昔芬耐药 ER 乳腺癌中的 mTOR 翻译控制通路

基本信息

批准号：
9889930
负责人：
Robert Schneider
金额：
$ 43.54万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889930
关键词：
Adjuvant Therapy Animals Aromatase Inhibitors Biopsy Specimen Breast Cancer Cell Breast Cancer cell line Breast cancer metastasis Cell Line Cell Survival Cessation of life Disease EGFR Protein Overexpression EIF4EBP1 gene Endocrine Epidermal Growth Factor Receptor Estrogen Receptor alpha Estrogen Receptors Estrogen Therapy Estrogen receptor positive FRAP1 gene Genetic Translation Indolent MAP Kinase Gene Mediating Mediator of activation protein Messenger RNA Modeling Pathway interactions Peptide Initiation Factors Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Postmenopause Premenopause Protein Kinase Recurrence Relapse Resistance Ribosomes Role Signal Transduction Tamoxifen Testing Toxic effect Translations Tumorigenicity Woman hormone therapy inhibitor/antagonist malignant breast neoplasm mortality neoplastic cell novel pre-clinical research response biomarker small molecule therapeutic target tumor tumor growth

项目摘要

Project Summary. Estrogen receptor positive (ER+) breast cancers comprise the majority (~70-80%) of breast cancers, the majority of late recurrences emanating from indolent or dormant breast cancer, and the majority of breast cancer deaths resulting from metastatic disease. Anti-endocrine therapy with tamoxifen remains the cornerstone of adjuvant therapy for ER+ breast cancers, particularly in premenopausal women, but also following treatment with aromatase inhibitors in the post-menopausal setting. Nevertheless, many women do not respond to tamoxifen in initial therapy, and of those that do, one third will relapse with resistant and metastatic disease within 15 years. Endocrine resistant ER+ breast cancers therefore remain one of the major causes of breast cancer metastasis and mortality. In fact, initial or acquired resistance to tamoxifen is involved in more than half of all ER+ breast cancer deaths. Reversing resistance to tamoxifen therapy is a crucial overarching breast cancer challenge. We provide preclinical research demonstrating the discovery of a crucial axis that provides tamoxifen resistance to ER+ breast cancer cells mediated by the epidermal growth factor receptor (EGFR)/estrogen receptor α (ERα) pathways, and their impact on selective mRNA translation through the kinase mTOR. Moreover, we demonstrate that there are several experimental drugs developed for other indications that can be repurposed to target this axis for the treatment of tamoxifen resistant ER+ breast cancers. Tamoxifen is an estrogen receptor antagonizing small molecule used for treatment for ER+ breast cancer worldwide. Resistance is well established to commonly involve overexpression of EGFRs on breast cancer cells, and hyper-activation or increased signaling of the MAPK-ERK and PI3K-Akt-mTOR pathways. We have now identified two novel hyperactivated mediators of resistance to tamoxifen therapy that lie at the intersection of these key pathways, and we show their importance in resistance. The two effectors of tamoxifen resistance are the inhibitor of translation initiation factor eIF4E, known as 4E-BP1, and the phosphorylation of eIF4E by hyper- activation of its ERK associated kinase, MNK1. Both are therapeutic targets for existing experimental drugs developed for other purposes with good toxicity profiles. eIF4E comprises the basic translation component for loading ribosomes onto mRNAs. Many studies by my group and others have shown that increased phosphorylation of eIF4E is controlled by the ERK-MNK1 pathway, and its increased abundance is controlled by the mTOR/4E-BP1 pathway, which selectively upregulates translation of specific mRNAs required for survival, proliferation and metastasis of breast cancer cells.

项目总结。雌激素受体阳性（ER+）乳腺癌占大多数（~70-80%）