Estrogen receptor 1 (ESR1, which encodes estrogen receptor-alpha) is a key driver gene for the initiation and progression of hormone receptor-positive breast cancer. Estrogen receptor-alpha (ER) is expressed in up to 70% of cases, and patients are routinely treated with endocrine therapies. However, the development of resistance over time is common and occurs in one-third of ER-positive breast tumors, leading to disease progression and death. X-box binding protein 1 (XBP1), a key component of the unfolded protein response (UPR) and ER signaling pathway, generates a positive feedback regulatory loop that leads to increased expression of XBP1 and ER in luminal breast cancer. In this review, we highlight new insights into the mechanisms of crosstalk between XBP1 and ER signaling and its clinical implications. Next, we describe the key signaling nodes that play an important role in XBP1-mediated endocrine resistance in breast cancer. Further, we discuss XBP1 gene mutations in breast cancer and the role of these mutations in the emergence of endocrine resistance and response to treatment. Finally, we discuss the current state and future directions for targeting XBP1 in combination with standard endocrine therapy to improve clinical outcomes in endocrine-resistant breast cancer patients.

中文翻译：

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靶向 IRE1-XBP1 轴克服乳腺癌内分泌抵抗：机遇与挑战。

雌激素受体 1（ESR1，编码雌激素受体-α）是激素受体阳性乳腺癌发生和进展的关键驱动基因。雌激素受体-α (ER) 在多达 70% 的病例中表达，患者常规接受内分泌治疗。然而，随着时间的推移，耐药性的发展很常见，并且发生在三分之一的 ER 阳性乳腺肿瘤中，导致疾病进展和死亡。X-box 结合蛋白 1 (XBP1) 是未折叠蛋白反应 (UPR) 和 ER 信号通路的关键组成部分，可产生正反馈调节回路，导致 XBP1 和 ER 在管腔乳腺癌中的表达增加。在这篇综述中，我们重点介绍了 XBP1 和 ER 信号传导之间的串扰机制及其临床意义的新见解。下一个，我们描述了在 XBP1 介导的乳腺癌内分泌抵抗中起重要作用的关键信号节点。此外，我们讨论了乳腺癌中的 XBP1 基因突变以及这些突变在出现内分泌抵抗和治疗反应中的作用。最后，我们讨论了靶向 XBP1 结合标准内分泌治疗以改善内分泌抵抗乳腺癌患者的临床结果的现状和未来方向。