Bone metastasis occurs in 70% of breast cancer patients and is a frequent cause of morbidity in cancer patients. A delicate balance exists in the bone microenvironment, but the functional dynamics underlying the tumor cell-microenvironment interactions remain poorly understood. 3D in vitro model systems of metastasis can throw new light on this phenomenon. Silk protein fibroin scaffolds, are cytocompatible for 3D cancer cell culture. They are structurally more resistant to protease degradation than other native biomaterials making these matrices suitable for cancer modeling. In this report, human breast adenocarcinoma cells, human osteoblast like cells and mesenchymal stem cells are co-cultered. Cancer cells and osteoblast-like cells are found to interact through secreted products. Decreased population of osteoblast-like cells and mineralization of extracellular matrix are observed as a result of co-culture. Significantly increased migration of breast cancer cells is observed in the bone-like constructs than in non-seeded scaffolds. The co-culture constructs show significant increase in drug resistance, invasiveness and angiogenicity. Co-culture of breast cancer cells with osteoblast like cells and mesenchymal stem cells also indicate that the interaction of cancer cells with bone microenvironment varies with spatial organization, presence of osteogenic factors as well as stromal cell type. Here, results show that 3D in vitro co-culture models is possibly a better system to study and target cancer progression.