Kosok Max, Alli-Shaik Asfa, Bay Boon Huat, Gunaratne Jayantha
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117594, Singapore.
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore.
iScience. 2020 Feb 21;23(2):100868. doi: 10.1016/j.isci.2020.100868. Epub 2020 Jan 28.
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer lacking targeted therapies. This is attributed to its high heterogeneity that complicates elucidation of its molecular aberrations. Here, we report identification of specific proteome expression profiles pertaining to two TNBC subclasses, basal A and basal B, through in-depth proteomics analysis of breast cancer cells. We observed that kinases and proteases displayed unique expression patterns within the subclasses. Systematic analyses of protein-protein interaction and co-regulation networks of these kinases and proteases unraveled dysregulated pathways and plausible targets for each TNBC subclass. Among these, we identified kinases AXL, PEAK1, and TGFBR2 and proteases FAP, UCHL1, and MMP2/14 as specific targets for basal B subclass, which represents the more aggressive TNBC cell lines. Our study highlights intricate mechanisms and distinct targets within TNBC and emphasizes that these have to be exploited in a subclass-specific manner rather than a one-for-all TNBC therapy.
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，缺乏靶向治疗方法。这归因于其高度异质性，使得阐明其分子畸变变得复杂。在此，我们报告通过对乳腺癌细胞进行深入的蛋白质组学分析，鉴定出与两种TNBC亚类（基底A和基底B）相关的特定蛋白质组表达谱。我们观察到激酶和蛋白酶在亚类中呈现出独特的表达模式。对这些激酶和蛋白酶的蛋白质-蛋白质相互作用及共调控网络进行系统分析，揭示了每个TNBC亚类失调的途径和可能的靶点。其中，我们鉴定出激酶AXL、PEAK1和TGFBR2以及蛋白酶FAP、UCHL1和MMP2/14是基底B亚类的特定靶点，基底B亚类代表更具侵袭性的TNBC细胞系。我们的研究突出了TNBC内部复杂的机制和不同的靶点，并强调必须以亚类特异性的方式加以利用，而不是采用一种适用于所有TNBC的治疗方法。
