While meant for wound healing and immunity in response to injury and infection, inflammatory signaling is usurped by cancerous tumors to promote disease progression, including treatment resistance. The interleukin-1 (IL-1) inflammatory cytokine family functions in wound healing and innate and adaptive immunity. Two major, closely related IL-1 family members, IL-1α and IL-1β, promote tumorigenic phenotypes and contribute to treatment resistance in cancer. IL-1 signaling converges on transactivation of the Nuclear Factor Kappa B (NF-κB) and Activator protein 1 (AP-1) transcription factors. NF-κB and AP-1 signaling are also activated by the inflammatory cytokine Tumor Necrosis Factor Alpha (TNFα) and microbe-sensing Toll-Like Receptors (TLRs). As reviewed elsewhere, IL-1, TNFα, and TLR can promote cancer progression through NF-κB or AP-1. In this review, we focus on what is known about the role of IL-1α and IL-1β in breast cancer (BCa) progression and therapeutic resistance, and state evidence for the role of NF-κB in mediating IL-1-induced BCa progression and therapeutic resistance. We will present evidence that IL-1 promotes BCa cell proliferation, BCa stem cell expansion, angiogenesis, and metastasis. IL-1 also regulates intracellular signaling and BCa cell hormone receptor expression in a manner that confers a growth advantage to the tumor cells and allows BCa cells to evade therapy. As such, the IL-1 receptor antagonist, anakinra, is in clinical trials to treat BCa and multiple other cancer types. This article presents a review of the literature from the 1990s to the present, outlining the evidence supporting a role for IL-1 and IL-1-NF-κB signaling in BCa progression.

Background/Objectives: The milieu of inflammatory cytokines present in the prostate cancer (PCa) tumor microenvironment exerts various effects on cancer progression. Chronic exposure to the inflammatory cytokine interleukin-1 (IL-1) has been shown to impact signaling via the RELA/NF-kB pathway; however, the effects of chronic inflammation on the integration of different inflammatory signaling pathways, such as the interleukin-6 (IL-6)/STAT3 axis, requires further exploration. Methods: We generated in vitro subline models by exposing the C4-2 and LNCaP PCa cell lines to either IL-1α or IL-1β for several months. We then treated the resulting sublines with acute IL-1 alone, IL-6 alone, or IL-1/IL-6 in combination and assessed for sensitivity to cytokine signaling. We observed changes in proliferation and quantified using Ki-67 immunostaining. Cell proliferation was assessed after siRNA silencing RELA or STAT3. Results: IL-1/IL-6 signaling in combination enhanced the signaling effects of either cytokine alone, particularly cytostasis. While the chronic IL-1 sublines maintained sensitivity to acute IL-6 signaling, they lost sensitivity to acute IL-1 signaling and did not show the enhanced IL-1/IL-6 cytostatic response. Inhibition of RELA and STAT3 rescued cytostasis after IL-1/IL-6 treatment in parental PCa cell lines, but only STAT3 inhibition rescued proliferation in the chronic IL-1 sublines. Conclusions: Our work shows that IL-1/RELA and IL-6/STAT3 work in parallel to synergistically induce cytostasis. However, chronic IL-1 exposure selects for cells that attenuate IL-1/RELA signaling, subsequently attenuating IL-1/IL-6 synergy.