Osteoprotegerin mediates tumor-promoting effects of Interleukin-1beta in breast cancer cells

Abstract

BackgroundIt 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 knockdown in breast cancer cells resulted in reduced invasion and metastasis. Here we present novel insight into the role of osteoprotegerin in inflammation-driven tumor progression in breast cancer by investigating the link between osteoprotegerin, macrophages and the potent pro-inflammatory cytokine Interleukin-1beta.MethodsWe used human breast cancer cell lines to investigate the effects of Interleukin-1beta treatment on osteoprotegerin secretion as measured by ELISA. We analyzed public datasets containing human breast cancer genome-wide mRNA expression data to reveal a significant and positive correlation between osteoprotegerin mRNA expression and the mRNA expression of Interleukin-1beta and of monocyte chemoattractant protein CC-chemokine ligand 2. Osteoprotegerin, Interleukin-1beta and CC-chemokine ligand 2 mRNA levels were also examined by qPCR on cDNA from normal and cancerous human breast tissue. We determined the effect of Interleukin-1beta–producing macrophages on osteoprotegerin expression by co-culturing breast cancer cells and differentiated THP-1 macrophages. Immunohistochemistry was performed on human breast tumor tissue microarrays to assess macrophage infiltration and osteoprotegerin expression. To demonstrate that osteoprotegerin mediated functional effects of Interleukin-1beta we performed cell invasion studies with control and OPG siRNA knockdown on Interleukin-1beta-treated breast cancer cells.ResultsWe report that Interleukin-1beta induces osteoprotegerin secretion, independent of breast cancer subtype and basal osteoprotegerin levels. Co-culture of breast cancer cells with Interleukin-1beta-secreting macrophages resulted in a similar increase in osteoprotegerin secretion in breast cancer cells as Interleukin-1beta treatment. Macrophage infiltration correlates with osteoprotegerin secretion in human breast tumor tissue samples. We show that osteoprotegerin secretion is regulated by Interleukin-1beta in a p38- and p42/44-dependent manner. We also demonstrate that osteoprotegerin knockdown represses Interleukin-1beta expression, Interleukin-1beta-mediated breast cancer cell invasion and MMP3 expression.ConclusionsThese data indicate a novel role for osteoprotegerin as a mediator of inflammation- promoted breast cancer progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0606-y) contains supplementary material, which is available to authorized users.

Prognostic Value of RANKL/OPG Serum Levels and Disseminated Tumor Cells in Nonmetastatic Breast Cancer

“…In breast cancer, higher concentrations of OPG were associated with an increased risk of ER-negative breast cancer (35). In addition, preclinical studies indicate that OPG mediates tumor-promoting effects as a mediator of inflammation in breast cancer (36) and promotes metastases in triple-negative breast cancer (37). Our data are in line with these results, implying that high levels of OPG, although potentially bone protective, actually confer a poor prognosis in certain malignancies including breast cancer.…”

An impedimetric molecularly-imprinted biosensor for Interleukin-1β determination, prepared by in-situ electropolymerization on carbon screen-printed electrodes

“…Interleukin-1β (IL-1β), a pro-inflammatory cytokine is implicated in cancer cell proliferation [1], emerging now as a key mediator of carcinogenesis. Its involvement in the molecular pathways of cancer-related inflammation are being unravelled, especially in pancreatic [2], breast [3] and prostate cancers [4]. Monitoring this biomarker in point-of care may therefore contribute to follow-up the progress of cancer diseases.…”

Osteoprotegerin: Relationship to Breast Cancer Risk and Prognosis

“…We have reported that there is an increase in OPG gene copy number in breast cancers and that this increase correlates with poor survival (38). In addition, we have shown that OPG expression is up-regulated in breast cancer cells cocultured with macrophages and this is in part due to the presence of Interleukin 1Beta (39). These studies demonstrate the potential for increased OPG expression in breast cancer, but the mechanisms for down-regulation with increasing tumor grade require further investigation.…”