Pujita Munnangi

Introduction. Breast cancer (BC) is the most prevalent form of cancer impacting women across the globe; 75% of patients with stage IV BC develop bone metastases.¹ Skeletal metastases lead to increased risk of fractures, weakened bones, severe pain and disability, and decreased mobility due to the development of osteolytic bone lesions.² These lesions develop due to a disturbance in equilibrium between osteoblast-mediated bone formation and osteoclast-mediated bone resorption.¹ Recent studies have shown the association of IL-1B, an inflammatory cytokine expressed in higher levels in BC, with bone metastases.³ IL-1B forms osteolytic bone lesions through interactions between tumor cells, osteoblasts, and osteoclasts.³ Targeting the IL-1B pathway with drugs such as IL-1R antagonist Anakinra and IL-1B antibody Canakinumab presents a way to decrease tumor progression.^1,3,4 Studies – Methods & Results. Tumor conditioned media was added to NAT1 and Wnt; effects were discerned using gene expression, osteoclastogenesis levels, cytokine array, and KEGG analysis.^5,6 Results showed NAT1 is an upstream regulator of IL-1B that leads to osteoclastogenesis.⁵ NAT1 inhibition is associated with lower IL-1B expression.⁵ Additionally, Wnt target gene AXIN2 expression is upregulated in BC cells.^5,6 Effects of Anakinra and Canakinumab were tested in-vivo in mice models implanted with 0.5-cm³ human femoral bone fragments in a separate study.³ BC cell lines transfected with IL1B/IL1R1 and control cells without IL1B/IL1R1 were implanted into mammary fat pads.³ IL1B, IL1R1, Caspase 1, and IL1Ra expression were measured.³ IL-1B was associated with bone metastasis formation in 7/10 control mice, 4/10 Anakinra-treated mice, and 1/10 Canakinumab-treated mice.³ Similar experiments were performed in a clinical trial testing Anakinra on 11 women with metastatic BC.⁷ Their blood was analyzed prior to, during, and after treatment for inflammatory signature.⁷ Analysis demonstrated lower gene expression of IL-1B, IL-1R1, and NF-κB.⁷ Another study showed the tumor-proliferating effects of IL-1B at the metastatic site and its anti-tumor effects at the primary cancer site.⁷ Conclusions. The IL-1B signaling pathway plays an important role in metastatic BC development. Increased NAT1 and TGF-β are associated with IL-1B upregulation, which leads to osteoclastogenesis through the IL-1B-NF-κB/CREB-Wnt axis. Targeting these pathways with drugs like Anakinra or Canakinumab may reduce metastasis. Since IL-1B acts paradoxically at primary and metastatic tumor sites, combination therapies must be used to treat patients in the most effective way possible.

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2. ‌Clézardin P, Coleman R, Puppo M, et al. Bone metastasis: mechanisms, therapies, and biomarkers. Physiological Reviews. 2021;101(3):797-855. doi:10.1152/physrev.00012.2019
3. ‌Tulotta C, Lefley DV, Freeman K, et al. Endogenous Production of IL1B by Breast Cancer Cells Drives Metastasis and Colonization of the Bone Microenvironment. Clinical cancer research : an official journal of the American Association for Cancer Research. 2019;25(9):2769-2782. doi:10.1158/1078-0432.CCR-18-2202
4. ‌Tulotta C, Ottewell P. The role of IL-1B in breast cancer bone metastasis. Endocrine-Related Cancer. 2018;25(7):R421-R434. doi:10.1530/erc-17-0309
5. Zhao C, Cai X, Wang Y, et al. NAT1 promotes osteolytic metastasis in luminal breast cancer by regulating the bone metastatic niche via NF-κB/IL-1B signaling pathway. American Journal of Cancer Research. 2020;10(8):2464-2479. Accessed March 2, 2022. https://pubmed.ncbi.nlm.nih.gov/32905535/
6. Eyre R, Alférez DG, Santiago-Gómez A, et al. Microenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling. Nature Communications. 2019;10(1). doi:10.1038/s41467-019-12807-0
7. Wu T-C, Xu K, Martinek J, et al. IL1 Receptor Antagonist Controls Transcriptional Signature of Inflammation in Patients with Metastatic Breast Cancer. Cancer Research. 2018;78(18):5243-5258. doi:10.1158/0008-5472.can-18-0413