G-quadruplex DNA structures mediate non-autonomous instruction of breast tumour microenvironments

Breast cancer is characterised by genetic and epigenetic alterations, such as G-quadruplex (G4) DNA secondary structures. Here, we uncover differentially enriched G4 structure-forming regions (∆G4Rs) and interlinked transcriptomes in the tumour microenvironment (TME) of breast cancer PDX models in vivo . We show that well-defined breast cancer cell models non-autonomously instruct ∆G4Rs and transcriptomes in the epigenomes of primary macrophages in vitro . Mechanistically, we uncover that TNBC secretes, amongst other factors, glucocorticoids to promote G4-linked activation of octamer-binding transcription factor 1 (OCT-1) and thereby reprogramme macrophages into an immunosuppressed and immunosuppressive state. This epigenetic mechanism is of clinical importance since instructed macrophages selectively associate with the triple-negative breast cancer (TNBC) basal-like 2 (BL2) subtype and with the distinct TNBC molecular signature derived from 2,000 primary breast cancer samples. Altogether, our data suggest that G4 formation is not only prevalent in breast cancer genomes but relevant in their TMEs as well, which is of clinical importance for cancer stratification and the discovery of novel actionable drivers.