Fig. 1: Interplay between oestrogen signalling and radiation on key cell signalling pathways.

(1) Radiation and excess oestrogens induce double strand DNA (dsDNA) breaks, directly and indirectly via production of reactive oxygen species. (2) Recognition of DNA damage by ATM/ATR induces DNA damage responses including DNA repair (homologous recombination repair and non-homologous end-joining) and cell cycle checkpoint arrest. This is achieved via activation of proteins including p53 and inhibition of CDKs/cyclins/CDC25A/c-myc. Oestrogen signalling can influence multiple points in these pathways, for example increasing expression/activity of CDKs/cyclin D1/CDC25A/c-myc whilst inhibiting tumour suppressor proteins such as Rb and p53, with the overall effect of cell cycle progression which may influence radiosensitivity. (3) dsDNA breaks lead to cytoplasmic dsDNA release which triggers cGAS/STING signalling. This typically leads to an acute type 1 interferon response which activates and attracts DCs/cytotoxic T-cells, but chronic or disrupted cGAS/STING signalling can lead to pro-tumour effects via non-canonical NF-kB signalling. cGAMP can be taken up by neighbouring immune cells and activate further cGAS/STING-mediated type 1 IFN responses. However, tumour cells may upregulate CD73/ENPP1 to convert extracellular cGAMP to adenosine, with immunosuppressive consequences. Type 1 interferon/STAT1 signalling can also increase Trex1 levels as part of a self-regulatory feedback loop. (4) Type 1 interferons (e.g. IFN-β) released in response to radiation increase expression of interferon-stimulated genes via JAK/STAT signalling. Oestrogen signalling can inhibit type 1 IFN responses by inhibition of STAT2 and exerts other non-genomic effects on cells including upregulation key oncogenic pathways including EGFR/MAPK and PI3K/AKT. There is also complex context-dependent cross-talk between transcriptional activity of oestrogen receptors and NF-kB. (5) Radiation triggers release of DAMPs which can promote DC activation. Radiation can also increase MHC-I expression on cells which increases recognition by immune cells, but oestrogen signalling and radiation can both lead to PD-L1 upregulation on tumour cells which reduces T-cell activation. Finally, radiation and oestrogen signalling can both increase release of TNF-α which has further impacts on NF-kB signalling. ES oestrogen signalling, dsDNA double-strand DNA, DAMPs damage-associated molecular patterns, HRR homologous recombination repair, NHEJ non-homologous end-joining, ROS reactive oxygen species, IFNs interferons, IFN-Rs interferon receptors, DC dendritic cell, CDK cyclin-dependent kinase.