Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60513, USA.
Department of Oncological Sciences, Huntsman Cancer Center, University of Utah, Salt Lake City, UT 84112, USA.
Endocrinology. 2024 Apr 29;165(6). doi: 10.1210/endocr/bqae051.
Annual breast cancer (BCa) deaths have declined since its apex in 1989 concomitant with widespread adoption of hormone therapies that target estrogen receptor alpha (ERα), the prominent nuclear receptor expressed in ∼80% of BCa. However, up to ∼50% of patients who are ER+ with high-risk disease experience post endocrine therapy relapse and metastasis to distant organs. The vast majority of BCa mortality occurs in this setting, highlighting the inadequacy of current therapies. Genomic abnormalities to ESR1, the gene encoding ERα, emerge under prolonged selective pressure to enable endocrine therapy resistance. These genetic lesions include focal gene amplifications, hotspot missense mutations in the ligand binding domain, truncations, fusions, and complex interactions with other nuclear receptors. Tumor cells utilize aberrant ERα activity to proliferate, spread, and evade therapy in BCa as well as other cancers. Cutting edge studies on ERα structural and transcriptional relationships are being harnessed to produce new therapies that have shown benefits in patients with ESR1 hotspot mutations. In this review we discuss the history of ERα, current research unlocking unknown aspects of ERα signaling including the structural basis for receptor antagonism, and future directions of ESR1 investigation. In addition, we discuss the development of endocrine therapies from their inception to present day and survey new avenues of drug development to improve pharmaceutical profiles, targeting, and efficacy.
自 1989 年达到顶峰以来，每年死于乳腺癌 (BCa) 的人数有所下降，这与广泛采用针对雌激素受体α (ERα) 的激素治疗同时发生，ERα 是在大约 80%的 BCa 中表达的突出核受体。然而，高达约 50%的患有高危疾病且雌激素受体阳性 (ER+) 的患者在内分泌治疗后复发并转移到远处器官。绝大多数 BCa 死亡发生在这种情况下，突出了现有疗法的不足。在长期的选择性压力下，ESR1 基因（编码 ERα 的基因）出现了异常，从而产生了内分泌治疗耐药性。这些遗传病变包括基因局部扩增、配体结合域热点错义突变、截断、融合以及与其他核受体的复杂相互作用。肿瘤细胞利用异常的 ERα 活性在 BCa 以及其他癌症中增殖、扩散和逃避治疗。对 ERα 结构和转录关系的前沿研究正在被利用来产生新的治疗方法，这些方法已显示出对 ESR1 热点突变患者的益处。在这篇综述中，我们讨论了 ERα 的历史，目前正在解锁 ERα 信号未知方面的研究，包括受体拮抗的结构基础，以及 ESR1 研究的未来方向。此外，我们讨论了从最初到现在的内分泌治疗的发展，并调查了改善药物特性、靶向和疗效的新药开发新途径。
