Identification of osteopontin-dependent signaling pathways in a mouse model of human breast cancer.

Background: Osteopontin (OPN) is a secreted phosphoprotein which functions as a cell attachment protein and cytokine that signals through two cell adhesion molecules, alphavbeta3-integrin and CD44, to regulate cancer growth and metastasis. However, the signaling pathways associated with OPN have not been extensively characterized. In an in vivo xenograft model of MDA-MB-231 human breast cancer, we have previously demonstrated that ablation of circulating OPN with an RNA aptamer blocks interaction with its cell surface receptors to significantly inhibit adhesion, migration and invasion in vitro and local progression and distant metastases.

Findings: In this study, we performed microarray analysis to compare the transcriptomes of primary tumor in the presence and absence of aptamer ablation of OPN. The results were corroborated with RT-PCR and Western blot analysis. Our results demonstrate that ablation of OPN cell surface receptor binding is associated with significant alteration in gene and protein expression critical in apoptosis, vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), interleukin-10 (IL-10), granulocyte-macrophage colony stimulating factor (GM-CSF) and proliferation signaling pathways. Many of these proteins have not been previously associated with OPN.

Conclusion: We conclude that secreted OPN regulates multiple signaling pathways critical for local tumor progression.