Mechanisms of tamoxifen-associated endometrial cancer risk

他莫昔芬相关子宫内膜癌风险的机制

• 批准号: 10650054
• 负责人: Jason Gertz
• 金额: $ 21.59万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650054
• 关键词: 4-Hydroxy-Tamoxifen; Accounting; Agonist; Antineoplastic Agents; Binding; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; CRISPR/Cas technology; Cancer Patient; Cells; Cessation of life; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Data; Disease; Endometrial; Endometrial Carcinoma; Endometrium; Estradiol; Estrogen Receptor alpha; Estrogen receptor positive; Estrogens; Evaluation; Generations; Genes; Genetic Transcription; Genomic approach; Genomics; Goals; Growth; Hormonal; Incidence; Individual; Invaded; Knowledge; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; Methods; Molecular; Molecular Mechanisms of Action; Output; Patient-Focused Outcomes; Patients; Pharmacologic Substance; Phenotype; Play; Proliferating; Proteomics; Recommendation; Recurrence; Risk; Risk Factors; Risk Reduction; Role; Sampling; Selective Estrogen Receptor Modulators; Seminal; Survival Rate; Tamoxifen; Techniques; Technology; Testing; Uterus; Woman; antagonist; cancer cell; cancer risk; cancer type; cell growth; cofactor; cohort; drug development; effective therapy; experimental study; gene discovery; genetic approach; genome editing; genome-wide; growth promoting activity; high risk; improved; innovation; insight; knock-down; malignant breast neoplasm; migration; mortality; new therapeutic target; next generation; novel; novel strategies; novel therapeutic intervention; novel therapeutics; side effect; therapeutic target; treatment strategy; tumor; tumor progression

PROJECT SUMMARY Tamoxifen is the most prescribed cancer drug in the world. Tamoxifen is a selective estrogen receptor modulator (SERM) that is used to treat patients with breast tumors that express estrogen receptor alpha (ER), acting as a partial antagonist that blocks ER’s growth-promoting activity. The use of tamoxifen has greatly benefited breast cancer patients by significantly reducing the risk of recurrence. Unfortunately, several severe side effects accompany the recommended 5-10-year course of tamoxifen treatment, including increased risk of endometrial cancer. It has been shown that tamoxifen acts as an ER agonist in the endometrium and in endometrial cancer cells. However, despite the initial observation of tamoxifen-associated endometrial cancer more than 30 years ago, the molecular mechanisms remain poorly understood. The leading hypothesis is that different cofactors interact with ER upon tamoxifen binding and these cofactors differ between breast cancer cells and endometrial cells. In this proposal, we will address the decades-old question of how tamoxifen acts as an agonist in endometrial cells using cutting edge techniques. We will use two approaches to determine key factors that underlie tamoxifen’s differential actions in breast and endometrial cancer. In specific aim 1, we will focus on the cofactor hypothesis by applying RIME, which identifies co-occurring factors on chromatin, to breast cancer cells and our unique collection of endometrial cancer and normal endometrial samples that have undergone treatment with estradiol and 4-hydroxytamoxifen. In specific aim 2, we will cast a broader net by using CRISPR approaches to identify genes essential for tamoxifen’s ER agonist role in endometrial cells and compare results to similar studies in breast cancer cells. The successful completion of this project will lead to a mechanistic understanding of how tamoxifen has dichotomous roles, being both an effective breast cancer treatment and an endometrial cancer risk factor. This knowledge will aid in identifying alternative breast cancer treatment strategies that reduce the chance of developing a deadly side effect and will help in discovering new therapeutic targets for endometrial cancer patients.

项目摘要 他莫昔芬是世界上最常用的抗癌药物。他莫昔芬是一种选择性雌激素受体 调节剂（SERM），用于治疗表达雌激素受体α（ER）的乳腺肿瘤患者， 作为部分拮抗剂阻断ER的促生长活性。他莫昔芬的使用 通过显著降低复发风险使乳腺癌患者受益。不幸的是，一些严重的 副作用伴随着推荐的5-10年的他莫昔芬治疗过程，包括增加的风险， 子宫内膜癌已经表明，他莫昔芬在子宫内膜和子宫内膜异位症中作为ER激动剂起作用。 子宫内膜癌细胞然而，尽管最初观察到他莫昔芬相关的子宫内膜癌， 30多年前，对分子机制仍然知之甚少。主要的假设是， 不同的辅因子在他莫昔芬结合后与ER相互作用，并且这些辅因子在乳腺癌之间不同。 细胞和子宫内膜细胞。在这份提案中，我们将解决他莫昔芬如何发挥作用的几十年来的问题 作为子宫内膜细胞的激动剂。我们将使用两种方法来确定密钥 三苯氧胺在乳腺癌和子宫内膜癌中不同作用的基础因素。具体目标1： 通过应用识别染色质上共现因子的RIME， 乳腺癌细胞和我们独特的收集子宫内膜癌和正常子宫内膜样本， 接受雌二醇和4-羟基他莫昔芬治疗。在具体目标2中，我们将撒下更广泛的网， 使用CRISPR方法鉴定他莫昔芬在子宫内膜细胞中ER激动剂作用所必需的基因， 将结果与乳腺癌细胞中的类似研究进行比较。该项目的成功完成将导致 机械地理解他莫昔芬是如何具有二分作用的， 治疗和子宫内膜癌的危险因素。这些知识将有助于确定替代乳腺癌 治疗策略，减少发展致命的副作用的机会，并将有助于发现新的 子宫内膜癌患者的治疗靶点。