Transcriptomic Profiling of Breast Cancer Cells Induced by Tumor-Associated Macrophages Generates a Robust Prognostic Gene Signature

SIMPLE SUMMARY: Macrophage, as the most abundant non-cancerous cell in tumor and one of the major immune cells, plays a critical role in tumor. On the one hand, it is an essential part of immune function. On the other hand, tumor-associated macrophages (TAMs) promote tumorigenesis in multiple ways. To fully analyze TAMs impact on breast cancer and explore the underlying mechanism, we employed a simplified and indirect cell model to identify the genes regulated by TAMs and developed a prognostic gene signature based on them. The gene signature exhibited good prognostic ability in overall survival, distant metastasis-free survival and disease-free survival. It also related with various clinical and biological features of breast cancer, which further strengthens TAMs’ full dimensional role in breast cancer development, encouraging more therapies targeting TAMs and providing a prognostic gene signature with potential clinical applications. ABSTRACT: Breast cancer, one of the most prevalent neoplasms in the world, continues attracting worldwide attention. Macrophage, as the most abundant non-malignant cell in tumor, plays critical roles in both immune surveillance and tumorigenesis and has become a cell target of immunotherapy. Among all macrophages, tumor-associated macrophage (TAM) is regarded as the main force to promote tumorigenesis. To get an overall view of its impact on breast cancer, we employed a simplified and indirect coculturing cell model followed by RNA-sequencing to detect cancer cell’s transcriptomic response induced by TAM and a prognostic gene signature was constructed based on it. Evidence from both cell models and clinical samples strengthened TAM’s full-dimensional impact on breast cancer, involved in almost all known signal pathways dysregulated during tumorigenesis from transcription, translation and molecule transport to immune-related pathways. Consequently, the gene signature developed from these genes was tested to be powerful in prognostic prediction and associated with various clinical and biological features of breast cancer. Our study presented a more complete view of TAM’s impact on breast cancer, which strengthened its role as an important therapy target. A 45-gene signature from the TAM-regulated genes was developed and shown potential in clinical application.