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

## TL;DR

This study shows that TLR4 and AGER proteins are more active in inflammatory breast cancer, which could help improve diagnosis and treatment.

## Contribution

The study is the first to investigate TLR4 and AGER in inflammatory breast cancer and their association with prognosis.

## Key findings

- IBC samples showed higher TLR4 and AGER expression compared to non-IBC samples.
- High TLR4 and AGER levels were linked to worse metastasis-free survival in patients.
- AGER expression was associated with triple-negative breast cancer subtypes in IBC.

## Abstract

Inflammatory breast cancer is a rare and aggressive form of breast cancer, making it crucial to understand what drives its growth. This study focuses on two proteins, TLR4 and AGER, which are known to play roles in other types of breast cancer but have not been well-studied in inflammatory breast cancer. We want to find out if these proteins are more active in inflammatory breast cancer compared to other breast cancers and if they relate to how the cancer behaves. By studying these proteins, we aim to uncover new insights that may ultimately lead to improved methods for diagnosing, treating, and managing this complex disease. Understanding the roles of TLR4 and AGER could offer new targets for future therapies and improve outcomes for patients with inflammatory breast cancer.

Background/Objectives: 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. Methods: 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. TLR4 and AGER gene expression were investigated using the microarray transcriptomic dataset of IBC and non-IBC samples (Gene Expression Omnibus repository—GEO). Results: IBC samples showed higher TLR4 and AGER immunoexpression than the non-IBC group and were associated with obesity and Ki-67 expression (p < 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 (p = 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 TLR4 and AGER expression increased in IBC compared to non-IBC samples. Conclusions: 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.