Long Li, Wang Lei, Liang Yiran, Ye Fangzhou, Jin Yuhan, Luo Dan, Li Xiaoyan, Wang Yajie, Li Yaming, Han Dianwen, Chen Bing, Zhao Wenjing, Wang Lijuan, Yang Qifeng
Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, PR China; Department of Breast Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang 621000, PR China.
Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, PR China.
Transl Oncol. 2025 Feb;52:102241. doi: 10.1016/j.tranon.2024.102241. Epub 2024 Dec 13.
Taxane-based chemotherapy is the primary treatment for triple-negative breast cancer (TNBC), yet clinical outcomes remain unsatisfactory due to the persistence of chemoresistance. Identifying key factors that contribute to chemoresistance and understanding the associated molecular mechanisms is therefore essential.
The GEO databases were utilized to pinpoint factors related to chemoresistance, which were subsequently validated using clinical tissue samples. The role of UGCG in the malignant progression and chemoresistance of TNBC was assessed through various functional assays. Western blotting, qRT-PCR, and immunohistochemistry were employed to investigate the signaling pathways associated with UGCG in TNBC.
UGCG expression was notably elevated in chemoresistant breast cancer tissues and cells, as identified in GEO databases and confirmed through immunohistochemistry. Additionally, findings from our cohorts indicated that higher levels of UGCG expression correlated with a lower rate of pathological complete response (pCR), suggesting it could serve as an independent predictor of chemotherapy effectiveness. Gain- and loss-of-function experiments demonstrated that UGCG enhanced the proliferation, metastasis, and stemness of breast cancer cells. Furthermore, treatment with paclitaxel or docetaxel resulted in increased UGCG expression, which in turn reduced chemotherapy-induced cell apoptosis and improved drug resistance and metastatic capabilities. Mechanistically, UGCG was found to amplify the activation of NF-κB and Wnt/β-catenin pathways, and the use of inhibitors targeting these pathways diminished the UGCG-induced malignant effects.
Our findings underscore the significant role of UGCG in the chemoresistance and progression of breast cancer, suggesting it as a predictive biomarker and potential therapeutic target to combat chemoresistance in this disease.
基于紫杉烷的化疗是三阴性乳腺癌（TNBC）的主要治疗方法，但由于化疗耐药性的持续存在，临床疗效仍不尽人意。因此，确定导致化疗耐药的关键因素并了解相关分子机制至关重要。
利用GEO数据库确定与化疗耐药相关的因素，随后使用临床组织样本进行验证。通过各种功能试验评估UGCG在TNBC恶性进展和化疗耐药中的作用。采用蛋白质免疫印迹法、qRT-PCR和免疫组织化学法研究TNBC中与UGCG相关的信号通路。
如在GEO数据库中所确定并通过免疫组织化学证实，UGCG在化疗耐药的乳腺癌组织和细胞中表达显著升高。此外，我们队列的研究结果表明，较高水平的UGCG表达与较低的病理完全缓解率（pCR）相关，提示其可作为化疗疗效的独立预测指标。功能获得和缺失实验表明，UGCG增强了乳腺癌细胞的增殖、转移和干性。此外，紫杉醇或多西他赛治疗导致UGCG表达增加，进而减少化疗诱导的细胞凋亡，提高耐药性和转移能力。机制上，发现UGCG可放大NF-κB和Wnt/β-连环蛋白信号通路的激活，使用针对这些信号通路的抑制剂可减弱UGCG诱导的恶性效应。
我们的研究结果强调了UGCG在乳腺癌化疗耐药和进展中的重要作用，提示其作为预测生物标志物和对抗该疾病化疗耐药的潜在治疗靶点。
