Abstract
Inflammasome complexes play a pivotal role in different cancer types. NOD-like receptor protein 3 (NLRP3) inflammasome is one of the most well-studied inflammasomes. Activation of the NLRP3 inflammasome induces abnormal secretion of soluble cytokines, generating advantageous inflammatory surroundings that support tumor growth. The expression levels of the NLRP3, PYCARD and TLR4 were determined by immunohistochemistry in a cohort of primary invasive breast carcinomas (BCs). We observed different NLRP3 and PYCARD expressions in non-tumor vs tumor areas (p<0.0001). All the proteins were associated to more aggressive clinicopathological characteristics (tumor size, grade, tumor proliferative activity etc.). Univariate analyses were carried out and related Kaplan-Meier curves plotted for NLRP3, PYCARD and TLR4 expression. Patients with higher NLRP3 and TLR4 expression had worse 5-year disease-free survival (DFS) compared to patients with lower NLRP3 and TLR4 expression (p =0.021 and p = 0.009, respectively). In multivariate analysis, TLR4 was confirmed as independent prognostic factors for DFS (HR = 2.03, 95% CI 1.16–3.57, p = 0.014), and high NLRP3 expression showed a slight association with DFS (HR = 1.75, 95% CI 0.98–3.15, p = 0.06). In conclusion, we showed TLR4 expression as independent prognostic factors and we highlighted for the first time that high expression of NLRP3 is linked to a poor prognosis in BC patients. These results suggest that NLRP3 and TLR4 could be two new good prognostic factor for BC patients.
Highlights
The tumor microenvironment (TME) is the result of a multistep process characterized by reprogramming across cellular components
High NOD-like receptor protein 3 (NLRP3), PYCARD and TLR4 expression was found in 31.8% (106/333), 38.6% (129/334) and 35.6% (115/323) of the tumor samples, respectively (Table 1)
NLRP3, PYCARD and TLR4 expression was evaluated according to their specific cut-off as described in the Material and Methods section
Summary
The tumor microenvironment (TME) is the result of a multistep process characterized by reprogramming across cellular components. Different critical oncogenic processes contribute to changing the TME, such as angiogenesis, invasion/metastasis, drug resistance and chronic inflammation [1]. Uncontrolled chronic inflammation has been shown to play a pivotal role in the onset and development of cancer via the up-regulation of growth factors, free radicals, prostaglandins and pro-inflammatory cytokines [interleukin (IL)-1b and IL-18] [2, 3]. NLRP3 Inflammasome in Breast Cancer cells can produce inflammatory mediators as well as fibroblasts, immune and endothelial cells [4]. The inflammatory microenvironment can contribute to enhancing mutational state and mutated cell proliferation. The triggers and molecular signaling implicated in the inflammatory state are still poorly characterized
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