Prognostic Value of NLRP3 Inflammasome and TLR4 Expression in Breast Cancer Patients

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.

Downstream Signaling of Inflammasome Pathway Affects Patients’ Outcome in the Context of Distinct Molecular Breast Cancer Subtypes

“…Our recent data demonstrated a higher NLRP3 and PYCARD expression in the tumor compartment with respect to the non-tumor areas in a BC cohort [14]. Here, we confirm the high NLRP3 and PYCARD expression in tumor samples (50% and 31%, respectively) as well as an overexpression of CyclinD1 and MYC, (48% and 32%, respectively).…”

“…Our previous study demonstrated the overexpression of NLRP3 in the tumor compartment compared to the non-tumor area in primary invasive BCs and its impact on disease free survival (DFS). In fact, high NLRP3 expression was associated with a worst DFS in this BC cohort [14]. Inflammasome crosses different pathways involved in cancer progression, including the Wnt/β-catenin/CyclinD1 signaling.…”

“…Tissue microarrays (TMAs) were prepared and IHC was performed as previously reported [14]. Consecutive sections of 4-µm thickness were cut from formalin-fixed and paraffin-embedded histological material and stained with an indirect immunoperoxidase method using the BenchMark XT automated staining instrument (Ventana Medical Systems, Tucson, AZ, USA) for NLRP3 and PYCARD, [14]. Antigen retrieval was made with Cell Conditioning solution 1 at 95 • for NLRP3 (32 min), and Cell Conditioning solution 2 at 95 • C for PYCARD (32 min).…”

Circular RNA circ_IRAK3 contributes to tumor growth through upregulating KIF2A via adsorbing miR-603 in breast cancer

“…Subsequently, we predicted the downstream targets of miR-603 using the miRDB database. 6 genes (NFIB [ 27 ], ZEB2 [ 28 ], TLR4 [ 29 ], KDM7A [ 30 ], LASP1 [ 31 ], and KIF2A [ 32 ]) related to BC were selected as candidate targets for further analysis among all predicted target genes. Moreover, only KIF2A was repressed in both miR-603-overexpressing HCC70 and MDA-MB-231 cells, so KIF2A was selected for subsequent investigation (Additional file 3 : Fig.…”

The Role of the NLRP3 Inflammasome in HCC Carcinogenesis and Treatment: Harnessing Innate Immunity

“…The reduced expression of NLRP3 in colorectal cancer (CRC) tissue holds a positive predictive value [93]. Likewise, the upregulation of NLRP3 expression in breast cancer heralds a poorer five-year survival rate [94]. The capability of the NLRP3 inflammasome to promote an immune response provides the potential to predict the response to immunotherapy.…”