Studies of Osteotropism on Both Sides of the Breast Cancer–Bone Interaction

While important advances have been made in the treatment of breast cancer (BrCa), little progress has been made in developing therapies for metastasis to bone, a complication that signals entry of the disease into an incurable phase. The process of identifying genes and gene signatures of BrCa associated with metastasis has begun. In contrast, knowledge of the contributions of bone to tumor-stroma interaction is still rudimentary. We are performing research designed to elucidate the mechanisms by which human BrCa metastasizes to bone (osteotropism). With evidence mounting that there is mutual recognition of BrCa and bone, we are investigating osteotropism from both sides of the tumor-stroma interface. We created a novel "all human" model in which human bone is transplanted into immunodeficient (NOD/SCID) mice. Human BrCa cells are injected into the mammary fat pad. Metastases later appear as metastases in the human bone, but not mouse skeleton. The model recapitulates the metastatic sequence occurring in patients. Using DNA microarrays, we plan to identify putative osteotropic genes expressed by metastatic BrCa cells. We will test the hypothesis that distinct "tool kits" are used by BrCa metastasizing to human bone. In addition, using human tissue-engineered bone, we are identifying components within bone stroma essential for metastasis, and osteotropism genes expressed by bone in response to the presence of BrCa. We recently demonstrated that tissue-engineered bone based on a silk sponge platform is a target for human BrCa metastasis, even in preference to the mouse skeleton.