Université de Lyon, Lyon, France.
Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
Life Sci Alliance. 2023 Aug 3;6(10). doi: 10.26508/lsa.202302009. Print 2023 Oct.
Triple-negative breast cancers (TNBCs) are the most aggressive breast cancers, and therapeutic options mainly rely on chemotherapy and immunotherapy. Although synthetic glucocorticoids (GCs) are given to alleviate the side effects of these treatments, GCs and their receptor, the glucocorticoid receptor (GR), were recently associated with detrimental effects, albeit the mechanisms involved remain elusive. Here, we identified the arginine methyltransferase PRMT5 as a master coregulator of GR, serving as a scaffold protein to recruit phospho-HP1γ and subsequently RNA polymerase II, independently of its methyltransferase activity. Moreover, the GR/PRMT5/HP1γ complex regulated the transcription of GC-target genes involved in cell motility and triggering cell migration of human TNBC cells in vitro and in a zebrafish model. Of note, we observed that GR/PRMT5 interaction was low in primary tumors but significantly increased in residual tumors treated with chemotherapy and GCs in neoadjuvant setting. These data suggest that the routine premedication prescription of GCs for early TNBC patients should be further assessed and that this complex could potentially be modulated to specifically target deleterious GR effects.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌，治疗选择主要依赖于化疗和免疫疗法。尽管给予合成糖皮质激素（GC）以减轻这些治疗的副作用，但 GC 及其受体，即糖皮质激素受体（GR），最近与不利影响相关，尽管涉及的机制仍不清楚。在这里，我们确定精氨酸甲基转移酶 PRMT5 为 GR 的主要核心调节剂，作为一种支架蛋白，可招募磷酸化 HP1γ，随后招募 RNA 聚合酶 II，而不依赖其甲基转移酶活性。此外，GR/PRMT5/HP1γ 复合物调节涉及细胞迁移和触发体外人 TNBC 细胞以及斑马鱼模型中细胞迁移的 GC 靶基因的转录。值得注意的是，我们观察到，在新辅助治疗中用化疗和 GC 治疗的原发性肿瘤中，GR/PRMT5 相互作用较低，但在残留肿瘤中显著增加。这些数据表明，应进一步评估早期 TNBC 患者常规预用 GC 的处方，并且该复合物可能被潜在地调节以专门针对有害的 GR 作用。
