DMP1 Activates Osteolytic Cycle in a Tumor Environment
thesisposted on 10.12.2012, 00:00 by Asha S. Eapen
Bone metastasis is one of the skeletal malignancies that could be caused by breast cancer. Dentin matrix protein 1 (DMP1) is an acidic noncollagenous protein localized specifically in the mineralized matrix of bone and dentin. It is a multifunctional protein, involved in gene regulation (within the cell) and HAP nucleation (in the ECM). DMP1 is endocytosed by preosteoblasts, triggering the calcium dependent and calcium independent signaling pathways resulting in a series of downstream events leading to osteoblast differentiation. These signaling events facilitate the activation of a calcium dependent stress-induced p38 MAP kinase and a calcium independent integrin mediated ERK1/2 MAP kinase pathway resulting in the expression of downstream target genes such as Runx2 and osteocalcin. Results from this study have shown that the osteoblast cells upon differentiation secrete receptor activator of nuclear factor kappa B ligand (RANKL) that stimulates the differentiation of precursor monocytes to osteoclasts. The study also focuses on identifying the role of DMP1 in breast cancer cells that could enhance osteoclast formation thereby accelerating bone resportion. Thus, the study reveals a new mechanism by which DMP1 can activate the vicious cycle leading to the aggressive growth and behavior of the cancer cells. To address the mechanism by which DMP1 might contribute to the osteolytic process, DMP1 was overexpressed in the metastatic cancer cell line MDA MB231. Upregulation of markers like Runx2, MMP2, MMP9, RANKL, OPN, BSP, VEGF and the activation of Smad2/3 and MAP kinase pathways (p38 and ERK1/2 pathways) were observed in overexpressed cells. Results from this study have shown that DMP1 secreted by the breast cancer cells into the extracellular environment could stimulate the differentiation of osteoblasts, leading to the secretion of factors that signal monocytes to differentiate to osteoclast thus resulting in bone metastasis. Overall, the results obtained from this study identify a new role for DMP1 in the differentiation of breast cancer tumor cells that may be directly related to their metastatic potential.