Soluble TRAIL could enhance bone destruction acting on Rank-ligand in estrogen-independent human breast cancer cell line MDA-MB-231.

The development and spread of tumors is associated with the ability of malignant cells to avoid detection and subsequent elimination by the immune system, to grow in non-native sites and to avoid programmed or induced cell death. In addition to the well-described role of osteoprotegerin in the regulation of bone turnover, there is an emerging evidence that osteoprotegerin may have an additional function due to its ability to bind and inhibit the members of the tumor necrosis factor (TNF)-superfamily, such as TNF-alpha and TNF-related apoptosis inducing ligand (TRAIL). We have shown that the breast cancer cell line MDA-MB-231 produces a sufficient amount of osteoprotegerin to bind TRAIL, resulting in an upregulation of receptor activator factor kappa B ligand (RANKL) expression. In conclusion, the presence of osteoprotegerin, as secreted by this cell line, acting as a paracrine factor, could affect breast cancer RANKL production inducing an enhancement of osteolysis and the perpetuation of a vicious cycle. A better understanding of the complex tumor cell-host cell interactions in the bone microenvironment, and of the autocrine and paracrine effects of the secreted (from tumor cells) and released (from bone matrix) factors may facilitate development of effective strategies to inhibit disease progression.