Triple negative breast cancer (TNBC), with its lack of targeted therapies, shows the worst mortality rate among all breast cancer subtypes. Clusterin (CLU) is implicated to play important oncogenic roles in cancer via promoting various downstream oncogenic pathways. Here, protein kinase D3 (PRKD3) is defined to be a key regulator of CLU in promoting TNBC tumor growth. Mechanically, PRKD3 with kinase activity binding to CLU is critical for CLU protein stability via inhibiting CLU's lysosomal distribution and degradation. CLU and PRKD3 protein level are significantly elevated and positively correlated in collected TNBC tumor samples. CLU silencer (OGX‐011) and PRKDs inhibitor (CRT0066101) can both result in impressive tumor growth suppression in vitro and in vivo, suggesting targeting CLU and its key regulator‐PRKD3 are promisingly efficient against TNBC. Finally, secreted CLU (sCLU) is found to be elevated in serums from TNBC patients and reduced in serum from TNBC murine models post OGX‐011 and/or CRT0066101 treatment, suggesting serum sCLU is a promising blood‐based biomarker for clinical management of TNBC. Taken together, this study provides a thorough molecular basis as well as preclinical evidences for targeting CLU pathway as a new promising strategy against TNBC via revealing PRKD3 as the key regulator of CLU in TNBC.

中文翻译：

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蛋白激酶D3抑制Clusterin的溶酶体降解促进三阴性乳腺癌肿瘤生长。

缺乏针对性治疗的三阴性乳腺癌（TNBC）在所有乳腺癌亚型中显示出最差的死亡率。Clusterin（CLU）通过促进各种下游致癌途径，在癌症中起着重要的致癌作用。在这里，蛋白激酶D3（PRKD3）被定义为CLU在促进TNBC肿瘤生长中的关键调节剂。从机械上讲，具有激酶活性的CRK结合到CLU的PRKD3通过抑制CLU的溶酶体分布和降解对于CLU蛋白的稳定性至关重要。在收集的TNBC肿瘤样品中，CLU和PRKD3蛋白水平显着升高并呈正相关。CLU消音器（OGX‐011）和PRKDs抑制剂（CRT0066101）均可在体内外产生令人印象深刻的肿瘤生长抑制作用，这表明靶向CLU及其关键调节剂PRKD3对TNBC有望有效。最后，发现在OGX-011和/或CRT0066101治疗后，TNBC患者血清中的分泌CLU（sCLU）升高，而TNBC鼠模型中的血清CLU（sCLU）降低，这表明血清sCLU是用于TNBC临床管理的有前途的血液生物标记。两者合计，这项研究通过揭示PRKD3作为TNBC中CLU的关键调节剂，为靶向CLU途径作为针对TNBC的一种新的有希望的策略提供了透彻的分子基础和临床前证据。