Abstract 3814: Association of Toll-like receptor-4 (TLR4) expression with stage and grade in endometrial cancer

Abstract

Abstract Objectives: Toll-like receptors (TLRs) are known to initiate immune responses upon binding bacterial glycolipids and have been implicated in the pathogenesis of a variety of human diseases including cancer. It is thought that cancers may sabotage TLR signaling pathways leading to enhanced tumor cell invasion and immune surveillance evasion. Upon glycolipid binding, TLR4 induces the production of proinflammatory cytokines through the adaptor protein, MyD88. Although TLR4 expression has been evaluated in normal endometrium, it has not been well-characterized in endometrial cancer. Thus, we sought to assess TLR4 and MyD88 expression in endometrial cancer specimens. Methods: TLR4 and MyD88 expression was evaluated by immunohistochemistry in 82 formalin-fixed, paraffin-embedded endometrial cancer specimens and 14 specimens of benign endometrium. Tissue microarrays were constructed, and two cores were analyzed for each patient. Immunohistochemical staining was scored according to the intensity (1+ to 3+) and qualitative percent cells staining per core. A “histoscore” was calculated, based on multiplying these two determinants ranging from 0 to 300 (i.e. intensity x % labeled). Results were analyzed using the Student t-test and ANOVA. Results: TLR4 and MyD88 staining was localized in the cytoplasm of both the benign and malignant endometrium. TLR4 and MyD88 expression was highest in the atrophic endometrium (mean 276 & 251, respectively) and lowest in the secretory endometrium (mean 182 & 136, respectively) (p=0.0182 for TLR4; p=0.0043 for MyD88). Expression was intermediary in the proliferative endometrium (mean 214 for TLR4; p=0.0278) (mean 210 for MyD88; p=0.0520). Of the endometrial cancer specimens, 87% were of endometrioid histology, and 13% were of serous histology. 77% of these tumors were from women with early stage cancers (stage 1/2), and 24% were from patients with advanced stage disease (stage 3/4). 89% of the endometrial cancers expressed TLR4, and 91% expressed MyD88. Decreased TLR4 expression correlated with higher stage (mean 205 for stage 1/2 and 169 for stage 3/4; p=0.0163) and grade (mean 214 for G1 and 176 for G3; p=0.0165). TLR4 and MyD88 expression did not significantly differ between endometrioid and serous histologies. Conclusions: TLR4 and MyD88 are expressed in endometrial cancers, and decreased TLR4 expression was associated with advanced stage and higher grade. Thus, the TLR4 pathway may represent a novel therapeutic target in endometrial cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3814.