FIGURE 8.

The schematic shows that breast cancer cells express Hh ligands (Hh-L) that activate Hh signaling in pre-osteoclasts. Breast cancer cells also express OPN that can initiate signaling in pre-osteoclasts. The pre-osteoclasts respond to Hh-L secreted by the breast cancer cells as well as autocrine Hh signaling by expressing OPN and differentiating into mature osteoclasts (characterized by expression of MMP9 and CTSK) with increased resorptive activity. Breast cancer cells also express PTHrP in response to Hh signaling (Sterling et al. (47)). Thus, overall, Hh signaling-mediated expression of factors such as OPN and PTHrP cumulatively results in enhanced differentiation and resorptive activity of osteoclasts. The dotted lines denote implications from previously published literature, whereas the solid lines depict data from the present work.