Abstract P6-08-10: Osteoprotegerin mediates tumor-promoting effects of Interleukin-1beta in breast cancer cells

Abstract

Abstract It is widely recognized that inflammation promotes breast cancer invasion and metastasis. Given the complex nature of the breast tumor inflammatory microenvironment, much remains to be understood of the molecular mechanisms that govern these effects. We have previously shown that osteoprotegerin (OPG) knockdown in breast cancer cells resulted in reduced invasion and metastasis. Here we present novel insight into the role of OPG in inflammation-driven tumor progression in breast cancer cells by investigating the link between OPG and the potent pro-inflammatory cytokine IL1B (IL1B). We used human breast cancer cell lines to investigate the effects of IL1B treatment on OPG expression. We analyzed public datasets containing human breast cancer genome-wide mRNA expression data to reveal a significant and positive correlation between OPG mRNA expression and the mRNA expression of IL1B as well as CCL2 (a monocyte chemoattractant protein). We determined the effect of macrophages (which produce IL1B) on OPG expression by co-culturing breast cancer cells and differentiated THP-1 macrophages. In order to demonstrate that OPG mediated functional effects of IL1B we performed cell invasion studies with control and OPG siRNA knockdown breast cancer cells treated with IL1B. We report that OPG expression is induced by IL1B, independent of breast cancer subtype and basal OPG levels. Co-culture of breast cancer cells with IL1B-secreting macrophages resulted in a similar increase in OPG expression in breast cancer cells as IL1B treatment. We show that OPG expression is regulated by IL1B in a p38-dependent manner. We also demonstrate that OPG knockdown represses IL1B expression, IL1B-mediated breast cancer cell invasion and MMP3 expression.It is widely recognized that inflammation promotes breast cancer invasion and metastasis. Given the complex nature of the breast tumor inflammatory microenvironment, much remains to be understood of the molecular mechanisms that govern these effects. We have previously shown that osteoprotegerin (OPG) knockdown in breast cancer cells resulted in reduced invasion and metastasis. Here we present novel insight into the role of OPG in inflammation-driven tumor progression in breast cancer cells by investigating the link between OPG and the potent pro-inflammatory cytokine IL1B (IL1B). We used human breast cancer cell lines to investigate the effects of IL1B treatment on OPG expression. We analyzed public datasets containing human breast cancer genome-wide mRNA expression data to reveal a significant and positive correlation between OPG mRNA expression and the mRNA expression of IL1B as well as CCL2 (a monocyte chemoattractant protein). We determined the effect of macrophages (which produce IL1B) on OPG expression by co-culturing breast cancer cells and differentiated THP-1 macrophages. In order to demonstrate that OPG mediated functional effects of IL1B we performed cell invasion studies with control and OPG siRNA knockdown breast cancer cells treated with IL1B. We report that OPG expression is induced by IL1B, independent of breast cancer subtype and basal OPG levels. Co-culture of breast cancer cells with IL1B-secreting macrophages resulted in a similar increase in OPG expression in breast cancer cells as IL1B treatment. We show that OPG expression is regulated by IL1B in a p38-dependent manner. We also demonstrate that OPG knockdown represses IL1B expression, IL1B-mediated breast cancer cell invasion and MMP3 expression. Citation Format: Tsang Mui Chung S, Geerts D, Roseman K, Renaud A, Connelly L. Osteoprotegerin mediates tumor-promoting effects of Interleukin-1beta in breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-08-10.