Knowlson Catherine, Haddock Paula, Bingham Victoria, McQuaid Stephen, Mullan Paul B, Buckley Niamh E
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
School of Pharmacy, Queen's University Belfast, Belfast, UK.
Ther Adv Med Oncol. 2020 Mar 9;12:1758835920906047. doi: 10.1177/1758835920906047. eCollection 2020.
Triple negative breast cancer (TNBC) is the subset of breast cancer associated with the poorest outcome, and currently lacks targeted treatments. Standard of care (SoC) chemotherapy often consists of DNA damaging chemotherapies ± taxanes, with a range of responses observed. However, we currently lack biomarkers to predict this response and lack alternate treatment options.
Pin1 expression was modulated and proliferation and treatment response was studied. Pin1 expression was analysed in patient samples and correlated with clinical outcome.
In this study, we have shown that the prolyl isomerase, Pin1, which is highly expressed in TNBC, plays a key role in pathogenesis of the disease. Knockdown of Pin1 in TNBC resulted in cell death while the opposite is seen in normal cells. We revealed for the first time that loss of Pin1 leads to increased sensitivity to Taxol but only in the absence of functional BRCA1. Conversely, loss of Pin1 results in decreased sensitivity to DNA-damaging agents independent of BRCA1 status. Analysis of Pin1 gene or IHC-based expression in over 200 TNBC patient samples revealed a novel role for Pin1 as a TNBC-specific biomarker, with high expression associated with improved outcome in the context of SoC chemotherapy. Preliminary data indicated this may be extended to other treatment options (e.g. Cisplatin/Parp Inhibitors) that are gaining traction for the treatment of TNBC.
This study highlights the important role played by Pin1 in TNBC and highlights the context-dependent functions in modulating cell growth and response to treatment.
三阴性乳腺癌（TNBC）是乳腺癌中预后最差的亚型，目前缺乏靶向治疗方法。标准护理（SoC）化疗通常包括DNA损伤化疗药物±紫杉烷类，观察到的反应范围较广。然而，我们目前缺乏预测这种反应的生物标志物，也缺乏替代治疗方案。
调节Pin1表达并研究增殖和治疗反应。在患者样本中分析Pin1表达并与临床结果相关联。
在本研究中，我们表明脯氨酰异构酶Pin1在TNBC中高表达，在该疾病的发病机制中起关键作用。在TNBC中敲低Pin1导致细胞死亡，而在正常细胞中则相反。我们首次揭示，Pin1缺失导致对紫杉醇的敏感性增加，但仅在缺乏功能性BRCA1的情况下如此。相反，Pin1缺失导致对DNA损伤剂的敏感性降低，与BRCA1状态无关。对200多个TNBC患者样本中Pin1基因或基于免疫组化的表达分析揭示了Pin1作为TNBC特异性生物标志物的新作用，在SoC化疗的背景下，高表达与更好的预后相关。初步数据表明，这可能扩展到其他正在获得TNBC治疗认可的治疗方案（如顺铂/聚ADP核糖聚合酶抑制剂）。
本研究突出了Pin1在TNBC中发挥的重要作用，并突出了其在调节细胞生长和治疗反应中的上下文依赖性功能。
