Mechanisms of tamoxifen-associated endometrial cancer risk

项目总结 他莫昔芬是世界上开得最多的抗癌药物。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。他莫昔芬的使用在很大程度上 通过显著降低复发风险，使乳腺癌患者受益。不幸的是，有几个严重的 副作用伴随着推荐的5-10年三苯氧胺疗程，包括增加 子宫内膜癌。已有研究表明，他莫昔芬在子宫内膜和子宫内膜中起ER激动剂的作用。 子宫内膜癌细胞。然而，尽管初步观察到他莫昔芬相关的子宫内膜癌 30多年前，人们对其分子机制仍知之甚少。主要的假设是 不同的辅因子与他莫昔芬结合后与ER相互作用，这些辅因子在乳腺癌之间存在差异 细胞和子宫内膜细胞。在这项提案中，我们将解决几十年来他莫昔芬如何起作用的问题 作为一种激动剂在子宫内膜细胞中使用尖端技术。我们将使用两种方法来确定密钥 他莫昔芬在乳腺癌和子宫内膜癌中不同作用的基础因素。在具体目标1中，我们将 通过应用RIME来关注辅助因子假设，RIME识别染色质上的共生因素 乳腺癌细胞和我们收集的独特的子宫内膜癌和正常子宫内膜样本 用雌二醇和4-羟基他莫昔芬治疗。在具体目标2中，我们将在以下方面撒网 使用CRISPR方法确定他莫昔芬在子宫内膜细胞和子宫内膜上扮演ER激动剂角色所必需的基因 将结果与对乳腺癌细胞的类似研究进行比较。这一项目的成功完成将导致 对他莫昔芬作为一种有效的乳腺癌的两种作用的机械性理解 治疗和子宫内膜癌的危险因素。这一知识将有助于识别另一种乳腺癌 减少发生致命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。

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.