Targeting Constitutively Active SUMO Modified Androgen Receptors in Endocrine Resistant Breast Cancer

项目总结 40%最常见的腔激素受体阳性(HR)乳腺癌(BCA)患者 亚型对传统内分泌治疗(ET)无反应，且很容易出现无法治愈的转移 疾病。内毒素抵抗(ET-R)BCA患者表现出对雄激素受体(AR)的内分泌开关- 依赖于肿瘤的生长和转移。抗雄激素正在成为治疗其他疾病的有希望的疗法 晚期BCA亚型但令人惊讶的是，AR过度表达ET-R BCA细胞对AR没有反应 对抗者。我们的新发现表明，结构性活跃的AR积聚并逃避了 抗雄激素药恩扎鲁胺(Enz)。因此，当前项目的目标是设计一种治疗方法 有效靶向AR和防止ET-R BCA转移进展的策略。 我们证明，与其他癌症模型不同，AR的持续性相扑翻译后修饰(PTM) (SUMO-AR)天然存在于获得性和固有的ET-R BCA细胞中。相扑-PTM是一种关键的动态细胞 过程和相扑特异酶的失衡导致了包括基础和Myc在内的一些类型的BCA。 根据我们和其他人的报告，依赖BCA。独立于已建立的相扑酶系统，我们 在ET-R BCA中鉴定一种双重相扑泛素连接酶，该酶可用药并破坏相扑受体的稳定性。这项建议 将描述这种新的连接酶在ET-R BCA中的调控及其在Enz反应中的作用。我们的新数据 这表明构成相扑-AR的基因组活性需要与lncRNA相互作用。因此，我们将 描绘了SUMO-AR/LncRNA相互作用如何促进ET-R BCA细胞中非配体依赖的基因组活性。 最后，建议的研究将测试1)抑制AR活性或2)增强AR的独特方法 与当前标准Enz的降解率相比。在这个过程中，我们将产生新的治疗方法并评估 临床相关化合物，特别适用于晚期ET-R BCA。 始终如一地，项目的完成将验证需求并建立工具，以实现更全面 ET-R HR BCA中SUMO-AR的翻译研究

PROJECT SUMMARY Forty percent of patients with the most prevalent luminal hormone receptor positive (HR+) breast cancer (BCa) subtype are unresponsive to conventional endocrine therapy (ET) and readily present with incurable metastatic disease. Patients with ET resistant (ET-R) BCa exhibit an “endocrine-switch” to androgen receptor (AR)- dependent tumor growth and metastasis. Anti-androgens are emerging as promising therapy for other advanced BCa subtypes but surprisingly, AR overexpressing ET-R BCa cells are unresponsive to AR antagonists. Our new findings show constitutively active AR accumulate and evade the inhibitory actions of anti-androgen Enzalutamide (Enz). Hence, the objective of the current project is to design a therapeutic strategy to effectively target AR and prevent metastatic progression of ET-R BCa. We demonstrate that unlike other cancer models, persistent SUMO post-translational modification (PTM) of AR (SUMO-AR) occurs natively in acquired and intrinsic ET-R BCa cells. SUMO-PTM is a critical dynamic cellular process and an imbalance in SUMO-specific enzymes drive select types of BCa including basal and Myc- dependent BCa as reported by us and others. Independent of the established SUMO enzymatic system, we identify a dual SUMO-ubiquitin ligase that is druggable and destabilizes SUMO-AR in ET-R BCa. This proposal will delineate the regulatory control of this novel ligase in ET-R BCa and its role in Enz-response. Our new data suggests that constitutive SUMO-AR genomic activity requires interaction with a lncRNA. Hence, we will delineate how SUMO-AR/lncRNA interaction facilitates ligand-independent genomic activity in ET-R BCa cells. Finally, the proposed studies will test unique approaches to either 1) inhibit AR activity or 2) potentiate AR degradation versus the current standard Enz. In the process, we will generate novel therapeutics and evaluate clinically relevant compounds specifically for advanced ET-R BCa. Consistently, completion of the project will validate the need and establish the tools for more comprehensive translational studies on SUMO-AR in ET-R HR+ BCa.