Hu Chenyang, Zhang Shenghua, Duan Fugang, Huang Xinmei, Huang Jing, Zhu Zhu, Mo Xiaoning, Xu Weiyan, Wu Lina, Fan Zhimin, Qiu Xiaoyan
Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China.
Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China.
Breast Cancer Res. 2025 Jun 2;27(1):96. doi: 10.1186/s13058-025-02052-3.
Triple-negative breast cancer (TNBC) is among the most aggressive and lethal subtypes of breast cancer. To date, there are no effective targeted treatment targets. Sialylated IgG (SIA-IgG), with unique sialylated modifications for N-glycosylation at site 162 of the heavy chain of IgG, which was found to be expressed in a variety of cancer cells as a novel procancer factor. Here, we aimed to investigate the expression frequency and procancer mechanisms of SIA-IgG in TNBC, and determine whether the SIA-IgG is a key factor that promotes TNBC and a novel target for TNBC therapy.
Immunohistochemical staining, immunofluorescence, and TCGA database analysis were performed to analyze the frequency of SIA-IgG expression in TNBC and the correlation between SIA-IgG expression and patient prognosis. Colony formation, transwell, and Matrigel-transwell assays were used to assess the proliferative and invasive abilities of SIA-IgG. Proteomic mass spectrometry and immunoprecipitation were utilized to identify the key procancer mechanisms of SIA-IgG. Oxygen consumption and extracellular acidification assays were used to elucidate the promotion of glucose metabolism and its mechanism in TNBC. Subcutaneous xenograft models were established to examine the antitumour effects of targeting SIA-IgG.
SIA-IgG was frequently detected in TNBC cells and was negatively associated with prognosis. Moreover, exogenously added SIA-IgG significantly enhanced the proliferation, migration and invasion of TNBC cells. Importantly, SIA-IgG significantly promoted TNBC progression by accelerating glycolysis and lactate reuse, which was dependent on its unique N-glycosylation at the Asn162 site. Conversely, the inhibition of SIA-IgG inhibited cancer cell proliferation and invasion by decreasing ATP and lactate production. Knockdown of SIA-IgG, as well as treatment with the anti-SIA-IgG antibody, significantly inhibited TNBC growth in vivo. Mechanistically, SIA-IgG promoted glycolysis and the lactate cycle mainly through the activation of two pathways: the integrin α6β4-FAK-AKT-HIF-1α-MCT4 axis, and the integrin α6β4-CD44-MCT1 axis.
These findings suggest that SIA-IgG, by enhancing glycolysis and the lactate cycle, induces metabolic reprogramming and thereby promotes the development of TNBC, making it a promising target for targeted therapy in TNBC.
三阴性乳腺癌（TNBC）是乳腺癌中侵袭性最强、致死率最高的亚型之一。迄今为止，尚无有效的靶向治疗靶点。唾液酸化IgG（SIA-IgG）在IgG重链第162位的N-糖基化具有独特的唾液酸化修饰，被发现作为一种新型促癌因子在多种癌细胞中表达。在此，我们旨在研究SIA-IgG在TNBC中的表达频率和促癌机制，并确定SIA-IgG是否是促进TNBC的关键因素以及TNBC治疗的新靶点。
进行免疫组织化学染色、免疫荧光和TCGA数据库分析，以分析TNBC中SIA-IgG的表达频率以及SIA-IgG表达与患者预后之间的相关性。采用集落形成、Transwell和基质胶Transwell实验评估SIA-IgG的增殖和侵袭能力。利用蛋白质组质谱和免疫沉淀技术鉴定SIA-IgG的关键促癌机制。通过耗氧和细胞外酸化实验阐明SIA-IgG对TNBC葡萄糖代谢的促进作用及其机制。建立皮下异种移植模型以检测靶向SIA-IgG的抗肿瘤作用。
在TNBC细胞中经常检测到SIA-IgG，且与预后呈负相关。此外，外源性添加SIA-IgG显著增强了TNBC细胞的增殖、迁移和侵袭能力。重要的是，SIA-IgG通过加速糖酵解和乳酸再利用显著促进TNBC进展，这依赖于其在Asn162位点独特的N-糖基化。相反，抑制SIA-IgG可通过降低ATP和乳酸生成来抑制癌细胞增殖和侵袭。敲低SIA-IgG以及用抗SIA-IgG抗体治疗均显著抑制TNBC在体内的生长。机制上，SIA-IgG主要通过激活两条途径促进糖酵解和乳酸循环：整合素α6β4-FAK-AKT-HIF-1α-MCT4轴和整合素α6β4-CD44-MCT1轴。
这些发现表明，SIA-IgG通过增强糖酵解和乳酸循环诱导代谢重编程，从而促进TNBC的发展，使其成为TNBC靶向治疗的一个有前景的靶点。
