The role of NF-kB in carcinogenesis and its connection with inflammation and chemoradioresistance of secondary edematous breast cancer and other malignant tumors (literature review and own research)

Background. The transcription factor NF-kB plays a pivotal role in various physiological processes, such as immune response, cell proliferation, apoptosis, and inflammation. It controls the transcriptional activity of numerous genes responsible for various pathways of inflammatory and oncological processes. Of particular interest are the signaling pathways regulated by NF-kB in carcinogenesis, angiogenesis, and tumor resistance to chemo- and radiotherapy. The interplay between oncological and inflammatory processes, accompanied by constitutive NF-kB activation, makes it a promising target for directed pharmacological intervention in cancer therapy. Purpose – to analyze current perspectives on the role of the transcription factor NF-kB in carcinogenesis, inflammation, and chemo- and radiotherapy resistance of tumors, and to assess its specific features in patients with secondary edematous breast cancer (SEBC). Materials and methods. The study presents data from our own research on 87 patients (42 with T4bN0-3M0 secondary edematous breast cancer (SEBC) and 45 with T3N0-3M0 breast cancer (BC)) aged 34–71 years (median 53.1) who were treated at the State Organization «Grigoriev Institute for Medical Radiology and Oncology of the National Academy of Medical Sciences of Ukraine». The control group consisted of 10 patients with fibroadenomas. The levels of IL-1B, IL-2, IL-6, IL-8, and TNF-α were measured using ELISA with «Vector-Best» kits in the serum of these patients. The content of NF-kB1 (p105 → p50) was also measured using ELISA with the «Human NF-kB – p105 ELISA Kit» and the «Immunochem-2100» analyzer (USA). Results. Based on literature data and our own research, NF-kB plays a key role in the functioning of many cancer cells through its activation and disruption of NF-kB signaling pathways. The NF-kB level was 9.8 times higher in patients with BC and 27.4 times higher in patients with SEBC than in patients from the control group with benign tumors. It was demonstrated that NF-kB plays a critical role in chronic inflammation, driving the link between inflammation and cancer by inducing proinflammatory cytokines such as IL-6, TNF-α, chemokine IL-8, and the COX-2 enzyme. The NF-kB level in the SEBC patient group with IL-6 and the group with TNF-α was 3.1 and 2.3 times higher than in patients of the respective BC groups. The highest level was found in the IL-8 group, where it was 5.7 times higher than in BC patients. Correlation analysis in SEBC patients revealed a significant relationship between NF-kB and IL-8 (r = 0.80; p < 0.05) and a less significant relationship between NF-kB and IL-6 (r = 0.60; p < 0.05), and between NF-kB and TNF-α (r = 0.60; p < 0.05). It was confirmed that NF-kB and the protein system associated with it, which is linked with the inflammatory cascade, control malignant transformation and its prevention. The possibility of targeting NF-kB for cancer treatment is being explored. Inhibition of the NF-kB activity can be achieved by influencing any of its activation stages. NF-kB serves as a marker for prediction and development of tumor resistance to radiation therapy in cancer patients, as well as a marker for developing NF-kB inhibition drugs. Conclusions. The analysis of literature data and our own research showed that activation of the transcription factor NF-kB plays a significant role in carcinogenesis and inflammation, and causes tumor chemoradioresistance. In SEBC, the highest NF-kB-p105 level was observed in the group with the highest IL-8 content. It was demonstrated that in SEBC patients, serum levels of NF-kB-p105, IL-6, IL-8, and TNF-α were significantly higher than in BC patients. These data indicate the highly aggressive nature of SEBC. NF-kB activity can be modulated using inhibitors that either target its activation pathways or directly block it. NF-kB, along with its role in the link between cancer and inflammation, can serve as a therapeutic target for suppressing tumor growth and sensitizing cancer cells to established cytotoxic anti-cancer therapy.