Mutual editing of alternative splicing between breast cancer cells and macrophages.

Breast cancer is a highly heterogeneous disease and numerous secreted factors may differentially contribute to a macrophage phenotype whose extensive infiltration is generally regarded as indicative of an unfavorable outcome. How different breast tumor cells and macrophage cells interplay or influence each other on the alternative splicing (AS) level have not been characterized. Here, we exploited one previous study, which investigated the interplay between macrophages and estrogen receptor-positive (ER+) breast cancer and triple-negative breast cancer (TNBC) at the transcriptional level, to investigate the tumor-macrophage crosstalk at the AS level. In the present study, it was demonstrated that biological processes such as DNA damage and DNA repair were significantly affected both in ER+ breast cancer and TNBC by co-culturing with macrophages, whereas biological pathways altered in macrophages co-cultured with tumor cells depended on the breast cancer type. Specifically, biological processes altered in macrophages co-cultured with ER+ breast cancer were enriched in RNA processing and translation-related pathways whereas biological processes altered in macrophages co-cultured with TNBC were mainly enriched in protein transport pathways. We also analyzed the sequence features of skip exons among different conditions. In addition, putative splicing factors which were responsible for the altered AS profile in each condition were identified. The findings of the present study revealed significant tumor-macrophage crosstalk at the AS level which may facilitate the development of new therapeutic strategies for cancer.