Induction of Increased Levels of Matrix Metalloproteinase-2 (MMP-2) and -9 in Human Breast Cancer Cell Lines by Activation of GM-CSF Receptor Bc via C-Fos-ERK 1/2 Signaling

Background and Objectives: Matrix metalloproteinase (MMP) -2 and -9 play important roles in the invasion and metastasis of breast cancer, but the mechanism of their regulation is not clearly understood. GM-CSF has been shown to be associated with cancer invasion and metastasis. The goal of our study was to examine the stimulation of GM-CSF/ interleukin 3 (IL-3)/IL-5 receptor common β-chain (βc) and its effects on MMP-2 and -9 regulation in human breast cancer cells.

Methods: The constitutive expression of the GM-CSF/IL-3/IL-5 receptor common βc and GM-CSF production were analyzed in BT 549, MCF-7, and MDA-MB 231 human breast cancer cell lines. We studied the effects of recombinant IL-3, IL-5 and GM-CSF on the gene expression and enzyme activity of MMP-2, and -9 in the aforementioned cell lines. The signaling pathway activated by these cytokines, the blocking of this pathway, and the effect on MMP-2 and -9 productions were also assessed. The downregulation of the GM-CSF receptor βc gene (CSF2RB) expression and its response to cytokine stimulation were also studied.

Results: We observed that the human breast cancer cell lines BT 549, MCF-7, and MDA-MB 231 constitutively produce GM-CSF and express the GM-CSF/IL-3/IL-5 receptor common βc. When these cell lines were treated with recombinant human (rh) GM-CSF, IL-3, and IL-5, enzyme activity and gene expression of MMP-2, and -9 were increased.

Conclusions: Our findings indicate that the activation of the c-Fos – ERK 1/2 signaling pathway upregulates MMP-2 in response to exogenous GM-CSF, IL-3 or IL-5 cytokines. Clinically relevant concentrations of GM-CSF (as low as 10 ng/mL) were sufficient to stimulate MMP-2 and -9. Our results suggest a potential mechanism by which GM-CSF may promote tumor invasion and metastases.