Toll-Like Receptor 3 Signaling in Breast Cancer
Michifumi Yamashita, Phillip E Bomeisl, Ganes C Sen, Hannah L Gilmore. University Hospitals Case Medical Center, Cleveland, OH; Case Western Reserve University, Cleveland, OH; Cleveland Clinic, Cleveland, OH
Background: Toll-like receptor 3 (TLR3) is a sensor for double-stranded (ds) RNA, a common byproduct of viral replication, and RNA from necrotic cells. A randomized clinical trial showed TLR3 stimulation therapy is effective for TLR3 positive breast cancer: it significantly decreased the risk of metastatic relapse in TLR3 positive breast cancer. Recently our group reported that 1) Epidermal Growth Factor Receptor (EGFR) is essential for TLR3 signaling (Sci Signal 2012), 2) TLR3 signaling suppresses cell migration and cell proliferation through TRIF-independent Src branch of TLR3 (J. Immnol 2012). EGFR and Src are essential components of TLR3. Theoretically, triple positive (TLR3, EGFR, and Src positive) breast cancer is good indication for the TLR3 stimulation therapy. However, the expression profile of these proteins in breast cancer, especially the relationship of these proteins in four breast cancer classes: Luminal A, Luminal B, HER2-enriched(HER2), and Basal-like (Basal), has not been studied yet.
Design: The expression levels of TLR3, EGFR, and Src in twenty-nine breast cancer tissues (10 Luminal A, 3 Luminal B, 2 HER2, and 14 Basal) were examined by immunohistochemistry on paraffin sections, and evaluated in blind manner.
Results: TLR3 is positive in 21/29 of total breast cancer cases (72.4%); 7/10 of Luminal A (70%), 2/3 of Luminal B (66.7%), 1/2 of HER2 (50%), and 11/14 of Basal (78.6%). EGFR is positive in 5/29 total cases (17.2%); 0/10 of Luminal A (0%), 1/3 of Luminal B (33.3%), 1/2 of HER2 (50%), and 3/14 of Basal (21.4%). Src is positive in 28/29 of total cases (96.6%); 10/10 of Luminal A (100%), 3/3 of Luminal B (100%), 2/2 of HER2 (100%), and 13/14 of Basal (92.9%). Triple positive staining was observed in 0/10 of Luminal A (0%), 1/3 of Luminal B (33.3%), 1/2 of HER2 (50%), and 2/14 of Basal (14.3%).
Conclusions: Majority of Luminal A expressed TLR3, but not EGFR. Some of other classes showed triple positive (TLR3, EGFR, and Src), suggesting TLR3 stimulation therapy is effective for some cases of Luminal B, HER2, and Basal, but not Luminal A. Now we are accumulating cases, and will be testing the effect of TLR3 stimulation on cell migration, a functional assay of cancer progression, using appropriate cell culture system with TLR3, EGFR, or Src know-down. This project will describe the detailed mechanism of TLR3 signaling in breast cancer, and will contribute to clinical development for a personalized anticancer therapy.
Wednesday, March 6, 2013 1:00 PM
Poster Session VI # 14, Wednesday Afternoon