Cancer-associated fibroblasts (CAFs) provide suitable conditions for growth of tumor cell and facilitate tumor progression. Hence, we aimed to identify a CAFs-related gene signature associated with the prognosis of patients with breast cancer (BRCA). We downloaded datasets from Gene Expression Omnibus (GEO) and confirmed the correlation between CAFs infiltration scores and prognosis. By performing weighted gene co-expression network analysis (WGCNA) and Lasso Cox regression analysis, we constructed a four-gene (COL5A3, FN1, POSTN, and RARRES2) prognostic CAFs signature model. Based on the median risk score of CAFs, patients with BRCA were divided into high- and low-risk groups. Compared with low-risk group, patients in high-risk group exhibited a poor prognosis and limited response to immunotherapy. Furthermore, patients with high CAFs risk scores were found to have a detrimental prognosis due to the induction of immunosuppressive cell infiltration, resulting in an immunosuppressive tumor microenvironment. Importantly, we found that CAFs overexpressing FN1 and POSTN significantly promoted the wound healing and invasion ability of tumor cells in vitro validation. Taking together, we identified a four-gene prognostic CAFs signature, which was proven to be a reliable indicator for prognosis and therapeutic efficacy in patients with BRCA. This study provided evidence for novel CAFs-based stromal therapy.

Background: Recent studies have shown that while chemotherapy kills tumor cells, it may also induce adaptive changes in cells within the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), which could paradoxically promote tumor progression. This study aimed to investigate the role of CAFs exposed to paclitaxel (PTX) or doxorubicin (DOX) in tumor progression and explore the underlying mechanisms. Methods: We examined the effects of PTX- or DOX-exposed CAFs on tumor migration and invasion through in vitro experiments. Bioinformatics analyses including Mendelian randomization, BayesPrism, and scPagwas were performed to elucidate the clinical relevance of IL-8 + CAFs in breast cancer. Additionally, in vitro experiments were conducted to confirm the tumor-promoting effects of CAFs-derived IL-8 and explore the underlying molecular mechanisms. Results: Our findings showed that CAFs exposed to PTX or DOX further promoted tumor migration and invasion compared to untreated CAFs. Notably, PTX and DOX significantly increased IL-8 expression levels in CAFs, suggesting that IL-8 may be a key cytokine mediating the tumor-promoting effect of CAFs exposed to chemotherapeutic agents. Interestingly, this tumor-promoting effect could be partly reversed by reparixin, an IL-8 receptor inhibitor. Mendelian randomization analysis confirmed that both IL-8 eQTL and plasma IL-8 levels were significantly associated with breast cancer risk. Further insights from BayesPrism and scPagwas indicated that IL-8 + CAFs were associated with clinical prognosis and may play a critical role in breast cancer progression. Furthermore, we confirmed the tumor-promoting effect of CAFs-derived IL-8. Mechanistically, IL-8 may modulate apoptosis by activating the NF-κB pathway, thereby inhibiting tumor cell apoptosis and leading to chemoresistance. Clinically, high IL-8 expression correlated with chemoresistance and poor survival in breast cancer patients. Conclusion: Our study suggests that the upregulation of IL-8 in CAFs following PTX or DOX treatment may contribute to chemotherapy-mediated tumor progression. These findings provide potential avenues for improving chemotherapy outcomes.

Affiliation [Department of Breast Surgery, Fengtai Maternal and Child Health Hospital, Beijing, China] was replaced with [The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China] for author "Xue Bai".The original version of this article has been updated.