Discipline of Pathology, Cancer Progression and Treatment Research Group, Lambe Institute for Translational Research, School of Medicine, University of Galway, H91TK33 Galway, Ireland.
Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, 40530 Gothenburg, Sweden.
Int J Mol Sci. 2023 Dec 22;25(1):186. doi: 10.3390/ijms25010186.
X-box binding protein 1 (XBP1) is a transcription factor that plays a crucial role in the unfolded protein response (UPR), a cellular stress response pathway involved in maintaining protein homeostasis in the endoplasmic reticulum (EnR). While the role of XBP1 in UPR is well-characterised, emerging evidence suggests its involvement in endocrine resistance in breast cancer. The transcriptional activity of spliced XBP1 (XBP1s) is a major component of its biological effects, but the targets of XBP1s in estrogen receptor (ER)-positive breast cancer are not well understood. Here, we show that the expression of miR-378 and PPARGC1B (host gene of miR-378) is downregulated during UPR. Using chemical and genetic methods, we show that XBP1s is necessary and sufficient for the downregulation of miR-378 and PPARGC1B. Our results show that overexpression of miR-378 significantly suppressed cell growth, colony formation, and migration of ER-positive breast cancer cells. Further, we found that expression of miR-378 sensitised the cells to UPR-induced cell death and anti-estrogens. The expression of miR-378 and PPARGC1B was downregulated in breast cancer, and higher expression of miR-378 is associated with better outcomes in ER-positive breast cancer. We found that miR-378 upregulates the expression of several genes that regulate type I interferon signalling. Analysis of separate cohorts of breast cancer patients showed that a gene signature derived from miR-378 upregulated genes showed a strong association with improved overall and recurrence-free survival in breast cancer. Our results suggest a growth-suppressive role for miR-378 in ER-positive breast cancer where downregulation of miR-378 by XBP1 contributes to endocrine resistance in ER-positive breast cancer.
X 盒结合蛋白 1（XBP1）是一种转录因子，在未折叠蛋白反应（UPR）中发挥关键作用，这是一种涉及内质网（EnR）中蛋白质稳态维持的细胞应激反应途径。虽然 XBP1 在 UPR 中的作用已经得到很好的描述，但新出现的证据表明它参与了乳腺癌的内分泌抵抗。剪接 XBP1（XBP1s）的转录活性是其生物学效应的主要组成部分，但 XBP1s 在雌激素受体（ER）阳性乳腺癌中的靶标尚不清楚。在这里，我们表明 miR-378 和 PPARGC1B（miR-378 的宿主基因）的表达在 UPR 期间下调。使用化学和遗传方法，我们表明 XBP1s 对于 miR-378 和 PPARGC1B 的下调是必需和充分的。我们的结果表明，miR-378 的过表达显著抑制了 ER 阳性乳腺癌细胞的生长、集落形成和迁移。此外，我们发现 miR-378 的表达使细胞对 UPR 诱导的细胞死亡和抗雌激素敏感。miR-378 和 PPARGC1B 在乳腺癌中的表达下调，miR-378 的高表达与 ER 阳性乳腺癌的更好结局相关。我们发现 miR-378 上调了几个调节 I 型干扰素信号的基因的表达。对乳腺癌患者的单独队列进行分析表明，源自 miR-378 上调基因的基因特征与乳腺癌患者的总生存期和无复发生存期的改善具有很强的相关性。我们的研究结果表明，miR-378 在 ER 阳性乳腺癌中具有生长抑制作用，而 XBP1 对 miR-378 的下调导致 ER 阳性乳腺癌的内分泌抵抗。
