Li Amber Xinyu, Zeng Jimmy Jianyuan, Martin Tracey A, Ye Lin, Ruge Fiona, Sanders Andrew J, Khan Elyas, Dou Q Ping, Davies Eleri, Jiang Wen G
Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
School of Natural and Social Science, University of Gloucestershire, Francis Close Hall, Cheltenham GL50 4AZ, UK.
Chin J Cancer Res. 2023 Aug 30;35(4):365-385. doi: 10.21147/j.issn.1000-9604.2023.04.04.
Striatins (STRNs) family, which contains three multi-domain scaffolding proteins, are cornerstones of the striatins interacting phosphatase and kinase (STRIPAK) complex. Although the role of the STRIPAK complex in cancer has become recognized in recent years, its clinical significance in breast cancer has not been fully established.
Using a freshly frozen breast cancer tissue cohort containing both cancerous and adjacent normal mammary tissues, we quantitatively evaluated the transcript-level expression of all members within the STRIPAK complex along with some key interacting and regulatory proteins of STRNs. The expression profile of each molecule and the integrated pattern of the complex members were assessed against the clinical-pathological factors of the patients. The Cancer Genome Atlas (TCGA) dataset was used to evaluate the breast cancer patients' response to chemotherapies. Four human breast cancer cell lines, MDA-MB-231, MDA-MB-361, MCF-7, and SK-BR-3, were subsequently adopted for work.
Here we found that high-level expressions of STRIP2, calmodulin, CCM3, MINK1 and SLMAP were respectively associated with shorter overall survival (OS) of patients. Although the similar pattern observed for STRN3, STRN4 and a contrary pattern observed for PPP2CA, PPP2CB and PPPR1A were not significant, the integrated expression profile of STRNs group and PPP2 group members constitutes a highly significant prognostic indicator for OS [P<0.001, hazard ratio (HR)=2.04, 95% confidence interval (95% CI), 1.36-3.07] and disease-free survival (DFS) (P=0.003, HR=1.40, 95% CI, 1.12-1.75). Reduced expression of STRN3 has an influence on the biological functions including adhesiveness and migration. In line with our clinical findings, the breast cancer cells responded to STRN3 knockdown with changes in their chemo-sensitivity, of which the response is also breast cancer subtype dependent.
Our results suggest a possible role of the STRIPAK complex in breast cancer development and prognosis. Among the members, the expression profile of STRN3 presents a valuable factor for assessing patients' responses to drug treatment.
条纹蛋白（STRNs）家族包含三种多结构域支架蛋白，是条纹蛋白相互作用磷酸酶和激酶（STRIPAK）复合体的基石。尽管近年来已认识到STRIPAK复合体在癌症中的作用，但其在乳腺癌中的临床意义尚未完全明确。
利用一个包含癌组织和相邻正常乳腺组织的新鲜冷冻乳腺癌组织队列，我们定量评估了STRIPAK复合体内所有成员以及STRNs的一些关键相互作用和调节蛋白的转录水平表达。根据患者的临床病理因素评估每个分子的表达谱和复合体内成员的整合模式。使用癌症基因组图谱（TCGA）数据集评估乳腺癌患者对化疗的反应。随后采用四种人乳腺癌细胞系MDA-MB-231、MDA-MB-361、MCF-7和SK-BR-3进行研究。
我们发现，STRIP2、钙调蛋白、CCM3、MINK1和SLMAP的高表达分别与患者较短的总生存期（OS）相关。尽管观察到的STRN3、STRN4的相似模式以及PPP2CA、PPP2CB和PPPR1A的相反模式不显著，但STRNs组和PPP2组成员的整合表达谱构成了OS[P<0.001，风险比（HR）=2.04，95%置信区间（95%CI），1.36 - 3.07]和无病生存期（DFS）（P = 0.003，HR = 1.40，95%CI，1.12 - 1.75）的高度显著预后指标。STRN3表达降低对包括黏附性和迁移在内的生物学功能有影响。与我们的临床发现一致，乳腺癌细胞对STRN3敲低的反应是化疗敏感性改变，且这种反应也依赖于乳腺癌亚型。
我们的结果提示STRIPAK复合体在乳腺癌发生发展和预后中可能发挥作用。在这些成员中，STRN3的表达谱是评估患者对药物治疗反应的一个有价值的因素。
