BRCA1 mutation promotes sprouting angiogenesis in inflammatory cancer-associated fibroblast of triple-negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with inferior outcomes owing to its low treatment response and high invasiveness. Based on abundant cancer-associated fibroblasts (CAFs) and frequent mutation of breast cancer-associated 1 (BRCA1) in TNBC, the characteristics of CAFs in TNBC patients with BRCA1 mutation compared to wild-type BRCA1 were investigated using single-cell analysis. Intriguingly, we observed a dominant presence of inflammatory CAFs (iCAFs) in BRCA1 mutation compared to the wild-type BRCA1 TNBC patients. iCAFs in patients with BRCA1 mutation exhibited strong signaling to endothelial cells (ECs) clusters, including chemokine (C-X-C motif) ligand 1 (CXCL) and vascular endothelial growth factor (VEGF). During CXCL signaling, the atypical chemokine receptor 1 (ACKR1) mainly interacts with CXCL family members in tumor endothelial cells (TECs). ACKR1-high TECs also showed high expression levels of angiogenesis related genes, such as ANGPT2, MMP1 and SELE, which might lead to EC migration. Furthermore, iCAFs showed VEGF signals for FLT1 and KDR in TECs, which showed high co-expression with tip cell marker genes, including ZEB1 and MAFF, involved in sprouting angiogenesis. Moreover, BRCA1 mutation patient with relatively abundant iCAFs and tip cell gene expression, exhibited a limited response to neoadjuvant chemotherapy, including cisplatin and bevacizumab. Importantly, our study observed the intricate link between iCAFs-mediated angiogenesis and chemoresistance in TNBC with BRCA1 mutation.