Tumor DNA-damage response (DDR) has an important role in driving type-I interferon (IFN)-mediated host antitumor immunity, but it is not clear how tumor DNA damage is interconnected with the immune response. Here, we report the role of IFN-g-inducible protein 16 (IFI16) in DNA repair, which amplifies the stimulator of IFN genes (STING)-type-I IFN signaling, particularly in triple-negative breast cancer (TNBC). IFI16 is rapidly induced and accumulated to the histone-evicted DNA at double-stranded breakage (DSB) sites, where it inhibits recruitment of DDR factors. Subsequently, IFI16 increases the release of DNA fragments to the cytoplasm and induces STING-mediated type-I IFN production. Synergistic cytotoxic and immunomodulatory effects of doxorubicin and type-I IFNs are decreased upon IFI16 depletion in vivo. Furthermore, IFI16 expression correlates with improved clinical outcome in patients with TNBC treated with chemotherapy. Together, our findings suggest that type-I IFNs and IFI16 could offer potential therapeutic strategies for TNBC.

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(1) Study Objectives: By investigating the change of cortisol levels during shift cycles among professional firefighters in Korea, this study aims to evaluate the difference between individuals’ stress response and the recovery of their circadian rhythm after working night shifts. (2) Methods: A total of 325 shift firefighters, who were working in 3, 6, 9, or 21 day cycles, participated in the study. Their urinary and serum cortisol levels were measured during the day (09–18), during the night (18–09), and every 24 h (09–09) per shift cycle, and adjustments were made for confounding factors. (3) Results: Serum cortisol levels were significantly increased after working during the night or for 24 h compared with that of working throughout the day. However, whether working night or 24 h shifts, the serum cortisol levels were undoubtedly different based on the 3, 6, 9, or 21 day cycles. In all shift cycles, the urinary cortisol level decreased during the night or throughout the 24 h shifts compared with sleeping during this time, but this was considered to be significantly applicable only to those working in 21 day cycles. Additionally, in serial measurements, the recovery of urinary cortisol secretion after a night or 24 h shift was successful for individuals working in 9 day cycles, but the recovery was delayed for those working in 6 or 21 day cycles. (4) Conclusions: After analyzing the urine cortisol levels, the study indicates that only subjects working in 9 day cycles fully recovered their circadian rhythm while those working in 6 day or 21 day cycles did not completely recover. Therefore, it is important to recognize how stressful night shifts can be, and it is crucial to enhance firefighters’ current shift cycles in order to allow sufficient recovery of their circadian rhythm as well as the prevention of disrupting their circadian rhythm after working at night. Further research is necessary to take into account the amount of work load, the challenges of being sleep deprived, and the individual’s capacity to overcome sleepiness.

Although type I interferons (IFNs) play multifaceted roles during tumorigenesis and cancer treatment, the interplay between type I IFNs and estrogen signaling in breast cancer (BC) microenvironment is not well understood. Here, we report a novel function of type I IFNs in inducing aromatase expression in adipose tissues surrounding BC, which potentiates the E2-dependent growth of estrogen receptor (ER)-positive BC. First, we found that expression levels of type I IFNs correlate negatively with clinical outcome but positively with tumor grade in patients with ER-positive BC. Levels of type I IFNs were elevated in cocultured media of immune cells and BC cells, which increased aromatase expression and E2 production in Simpson–Golabi–Behmel syndrome preadipocytes. The type I IFN-induced aromatase expression was dependent on IFN-γ-inducible protein 16 (IFI16), which is encoded by an interferon-stimulated gene. At the molecular level, type I IFNs led to recruitment of HIF1α–IFI16–PRMT2 complex to the hypoxia-response element located in the aromatase PI.3/PII promoter. Next, we generated an adipocyte-specific Ifi204, which is a mouse ortholog of human IFI16, knockout mouse (Ifi204-AKO). IFNβ induced E2 production in the preadipocytes isolated from the control mice, but such E2 production was far lower in the Ifi204-AKO preadipocytes. Importantly, the growth of orthotopically inoculated E0771 ER-positive mammary tumors was reduced significantly in the Ifi204-AKO mice. Taken together, our findings provide novel insights into the crosstalk between type I IFNs and estrogen signaling in the progression of ER-positive BC.