Wu Xiao, Liu Yameng, Hu Yinxi, Su Fang, Wang Zishu, Chen Yongxia, Zhuang Zhixiang
Department of Oncology, the Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Medical Oncology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, China.
Sci Rep. 2025 Apr 25;15(1):14535. doi: 10.1038/s41598-025-98661-1.
Leucine rich repeat containing 15 (LRRC15) is recognized for its intimate association with the extracellular matrix, where it modulates fibroblast function and shapes the immune landscape within the tumour microenvironment. The specific expression patterns and molecular contributions of LRRC15 in triple-negative breast cancer(TNBC) have not been fully elucidated. This study aimed to delineate the clinical relevance and biological implications of LRRC15 in TNBC, and to assess its potential as a novel therapeutic target for this disease. Our findings revealed robust overexpression of LRRC15 in TNBC tumour tissues and cell lines, which was inversely correlated with patient survival outcomes. Notably, the suppression of LRRC15 expression led to pronounced inhibition of TNBC cell proliferation, invasion, and migration both in vitro and in vivo. Mechanistically, we established that LRRC15 interacts with Integrin Beta 1(ITGB1), facilitating the phosphorylation of the T788/T789 residues on ITGB1 and recruiting focal adhesion kinase (FAK) to the site of integrin aggregation. This recruitment promotes the downstream phosphorylation of PI3K and AKT, suggesting that LRRC15 is a key activator of the ITGB1/FAK/PI3K signalling pathway. Collectively, our data indicate that LRRC15 is a critical promoter of TNBC cell proliferation and metastasis through the activation of this signalling pathway, identifying LRRC15 as a promising candidate for therapeutic intervention in TNBC.
富含亮氨酸重复序列15（LRRC15）因其与细胞外基质的密切关联而被人们所认识，在细胞外基质中，它调节成纤维细胞功能并塑造肿瘤微环境中的免疫格局。LRRC15在三阴性乳腺癌（TNBC）中的具体表达模式和分子作用尚未完全阐明。本研究旨在阐明LRRC15在TNBC中的临床相关性和生物学意义，并评估其作为该疾病新型治疗靶点的潜力。我们的研究结果显示，LRRC15在TNBC肿瘤组织和细胞系中大量过表达，这与患者的生存结果呈负相关。值得注意的是，抑制LRRC15的表达导致TNBC细胞在体外和体内的增殖、侵袭和迁移均受到明显抑制。从机制上讲，我们发现LRRC15与整合素β1（ITGB1）相互作用，促进ITGB1上T788/T789残基的磷酸化，并将粘着斑激酶（FAK）募集到整合素聚集位点。这种募集促进了PI3K和AKT的下游磷酸化，表明LRRC15是ITGB1/FAK/PI3K信号通路的关键激活剂。总体而言，我们的数据表明，LRRC15通过激活该信号通路是TNBC细胞增殖和转移的关键促进因子，确定LRRC15是TNBC治疗干预的一个有前景的候选靶点。
