School of Life Sciences, University of Hull, Hull, UK.
Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, The University of Oxford, Oxford, UK.
Br J Cancer. 2018 May;118(9):1229-1237. doi: 10.1038/s41416-018-0056-3. Epub 2018 Mar 15.
Metastatic spread is responsible for the majority of cancer-associated deaths. The tumour microenvironment, including hypoxia, is a major driver of metastasis. The aim of this study was to investigate the role of the E3 ligase WSB-1 in breast cancer biology in the context of the hypoxic tumour microenvironment, particularly regarding metastatic spread.
In this study, WSB-1 expression was evaluated in breast cancer cell lines and patient samples. In silico analyses were used to determine the impact of WSB-1 expression on distant metastasis-free survival (DMFS) in patients, and correlation between WSB1 expression and hypoxia gene expression signatures. The role of WSB-1 on metastasis promotion was evaluated in vitro and in vivo.
High WSB1 expression was associated with decreased DMFS in ER-breast cancer and PR-breast cancer patients. Surprisingly, WSB1 expression was not positively correlated with known hypoxic gene expression signatures in patient samples. Our study is the first to show that WSB-1 knockdown led to decreased metastatic potential in breast cancer hormone receptor-negative models in vitro and in vivo. WSB-1 knockdown was associated with decreased metalloproteinase (MMP) activity, vascular endothelial growth factor (VEGF) secretion, and angiogenic potential.
Our data suggests that WSB-1 may be an important regulator of aggressive metastatic disease in hormone receptor-negative breast cancer. WSB-1 could therefore represent a novel regulator and therapeutic target for secondary breast cancer in these patients.
转移扩散是导致大多数癌症相关死亡的主要原因。肿瘤微环境，包括缺氧，是转移的主要驱动因素。本研究旨在探讨 E3 连接酶 WSB-1 在缺氧肿瘤微环境中的作用及其在乳腺癌生物学中的作用，特别是在转移扩散方面。
在本研究中，评估了 WSB-1 在乳腺癌细胞系和患者样本中的表达。采用计算机分析来确定 WSB-1 表达对患者远处无转移生存（DMFS）的影响，以及 WSB1 表达与缺氧基因表达特征之间的相关性。在体外和体内评估了 WSB-1 对转移促进的作用。
高 WSB1 表达与 ER 阳性乳腺癌和 PR 阳性乳腺癌患者的 DMFS 降低相关。令人惊讶的是，WSB1 表达与患者样本中已知的缺氧基因表达特征没有正相关。本研究首次表明，WSB-1 敲低导致体外和体内激素受体阴性乳腺癌模型的转移潜能降低。WSB-1 敲低与基质金属蛋白酶（MMP）活性、血管内皮生长因子（VEGF）分泌和血管生成潜能降低有关。
我们的数据表明，WSB-1 可能是激素受体阴性乳腺癌侵袭性转移疾病的重要调节因子。因此，WSB-1 可以作为这些患者继发性乳腺癌的新型调节因子和治疗靶点。
