TLR signaling inhibitor, phenylmethimazole, in combination with tamoxifen inhibits human breast cancer cell viability and migration.

Anthony L Schwartz,Nilesh Dagia,Ramiro Malgor,Kelly D Mccall,Eric Dickerson

doi:10.18632/oncotarget.10358

Abstract

Heightened co-expression and dysregulated signaling associated with Toll-like receptor 3 (TLR3) and Wnt5a is an integral component of solid tumors and hematological malignancies. Our previous findings in pancreatic cancer and melanoma suggest that inhibition of these pathways by a TLR3 signaling inhibitor, phenylmethimazole (C10), results in significantly decreased IL-6 levels, STAT3 phosphorylation, minimal cancer cell migration and reduced cancer cell growth in vitro and in vivo. In this study, we extended our earlier observations by performing studies in human breast cancer cells. We found that human MCF-7 breast cancer cells express high basal levels of TLR3 and Wnt5a RNA. C10 treatment resulted in significantly decreased TLR3 and Wnt5a expression levels. This functionally translated into significantly reduced IL-6 levels and STAT3 phosphorylation in vitro. In addition, the inhibition of this signaling cascade by C10 further resulted in decreased cell viability and migration of MCF-7 cells. Strikingly, the combination of C10 and tamoxifen, the standard of care therapy for breast cancer, further decrease cancer cell growth better than either agent alone. These data support the novel finding that inhibition of TLR3 signaling in combination with tamoxifen, may increase the effectiveness of current treatments of breast cancer.

Highlights

Extensive research from in vitro, in vivo and clinical studies has established that Toll-like receptors (TLRs) are important in the development of carcinogenesis and tumor progression of a variety of cancers
Previous studies in our laboratory demonstrated that C10 decreased high constitutive Tolllike receptor 3 (TLR3) and Wnt5a expression in human malignant melanoma, papillary thyroid, and pancreatic cancer cell lines [1, 2]
In these studies we sought to evaluate the effect of the same TLR signaling inhibitor, C10, on human MCF-7 breast cancer cells that exhibit high constitutive levels of TLR3 and Wnt5a RNA

Summary

Introduction

Extensive research from in vitro, in vivo and clinical studies has established that Toll-like receptors (TLRs) are important in the development of carcinogenesis and tumor progression of a variety of cancers. Heightened expression of TLRs is evidenced in multiple cancer cell lines, and in tumor cells and tissues obtained from patients [1,2,3]. Much like TLRs, the Wnt family proteins have been implicated in carcinogenesis - in both the initiation and maintenance of cancer [5,6,7]. In vitro studies with various cancer cell lines and tumor specimens from patients have revealed elevated expression of Wnt proteins (e.g., Wnt5a) and deregulated Wnt signal transduction www.impactjournals.com/oncotarget pathways [5, 8,9,10,11]. The elevated expression of Wnt proteins (e.g., Wnt5a) in tumor samples correlates with advanced stages and poor prognosis in solid tumors as well as hematological malignancies [5, 8,9,10,11]

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Conclusion