Clinical Significance and Prognostic Value of TLR4 and AGER in Inflammatory Breast Cancer

Abstract

<b>Background/Objectives</b>: Inflammatory breast carcinoma (IBC) is an aggressive and rare neoplasm, accounting for 1-5% of all breast cancers. Toll-like receptor type 4 (TLR4) and Advanced Glycation End Products Receptor (AGER/RAGE) have been implicated in breast cancer, and have been shown to promote tumor growth, metastasis, and resistance to therapy by modulating the tumor microenvironment and inflammatory pathways. However, the role of TLR4 and AGER in IBC has not been elucidated. <b>Methods</b>: TLR4 and AGER immunofluorescence expression were evaluated in 27 IBC and 24 non-IBC samples. The expression data and clinicopathological parameters, including the prognostic values of these biomarkers, were compared. <i>TLR4</i> and <i>AGER</i> gene expression were investigated using the microarray transcriptomic dataset of IBC and non-IBC samples (Gene Expression Omnibus repository-GEO). <b>Results</b>: IBC samples showed higher TLR4 and AGER immunoexpression than the non-IBC group and were associated with obesity and Ki-67 expression (<i>p</i> &lt; 0.05). AGER expression in IBC versus non-IBC was also statistically associated with triple-negative molecular subtypes. Non-IBC subjects with AGER immunoexpression above the cutoff (106.1%, sensitivity of 92.3%, and specificity of 56.2%) showed reduced metastasis-free survival (<i>p</i> = 0.032). In the multivariate analysis, high TLR4 immunostaining increased the risk of metastasis-free survival by 1.029-fold. Analyzing three external GEO datasets confirmed that <i>TLR4</i> and <i>AGER</i> expression increased in IBC compared to non-IBC samples. <b>Conclusions</b>: Overall, IBC samples showed higher TLR4 and AGER expressions than other breast cancer types, shedding light on the significance of these markers on IBC biology.