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

// Anthony L. Schwartz 1 , Eric Dickerson 2 , Nilesh Dagia 3 , Ramiro Malgor 2 and Kelly D. McCall 4 1 Athencion Biotechnology Corporation, Suite 100, Marietta, OH 45750, USA 2 Department of Biomedical Sciences, Appalachian Rural Health Institute, Diabetes Research Center, College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA 3 Oxygen Healthcare Research Pvt. Ltd, Ahmedabad, Gujarat 382213, India 4 Department of Specialty Medicine, Appalachian Rural Health Institute, Diabetes Research Center, College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA Correspondence to: Kelly D. McCall, email: mccallk@ohio.edu Keywords: breast cancer, toll-like receptors, cytokines, tamoxifen, chemotherapy Received: December 01, 2015     Accepted: May 28, 2016     Published: July 01, 2016 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.