The presence of cells with molecular and morphological aspects of osteoblasts in several human breast and prostate cancers further confirmed this biological connection [2]. It is important to note that osteoblast-like cells (OBLs) were frequently described in epithelial cancers, suggesting a link with the epithelial to mesenchymal transition (EMT) phenomenon [2]. In our previous study, we demonstrated that the formation of osteoblast-like cells in breast tissues (BOLCs) is strictly related to the expression of the main EMT markers such as vimentin, CD44 and β-catenin [2, 3]. On note, BOLCs displayed functional affinity to osteoblasts since they produce calcified crystals made of hydroxyapatite [2]. The localization of such cancer cells around microcalcifications led us to hypothesize that breast cells, in presence of EMT inducer molecules, can acquire mesenchymal phenotypes, transforming themselves into OBLs capable of contributing to the production of ectopic calcifications [2, 4]. Nevertheless, the molecular mechanisms of cancer cells’ osteotropism remain undefined. Also, our recent data showed that breast cancer cells, that mimic osteoblasts by expressing bone matrix proteins and factors (BOLCs), have a higher likelihood of metastasizing to bone. In particular, BOLCs in primary lesions were characterized by the expression of bone markers such as vitamin D receptor, RANKL and RUNX2 [2]. Interestingly, we reported that the breast cancer microenvironment was characterized by the expression of molecules able to induce osteoblastic proliferation and differentiation. Specifically, we demonstrated that numerous breast cancer cells frequently express BMPs superfamily molecules, in particular BMP-2, BMP-4 and BMP-7. BMPs are a group of molecules initially discovered for their capability to induce the formation of cartilage and bone tissues [5]. A recent study has highlighted that BMPs constitute a cluster of morphogenetic signals, orchestrating tissue architecture throughout the body [5]. Furthermore, the central role of BMPs in physiology is emphasized by the association between dysregulated BMP signalling and pathological processes, such as EMT [6]. This evidence supports the idea that cancer microenvironments could represent a ‘primordial soup’for the development of OLCs. Indeed, it is also characterized by the expression of new and powerful osteoblastic inductor as PTX3 [7]. A very interesting study of Lacroix et al. indicates that breast cancer cells secrete factors that inhibit the growth of osteoblasts and increase their sensitivity to various osteolytic agents [8]. This evidence further supports the idea that BOLCs are essential for the development of the osteolytic bone metastasis typical of breast cancer. However, from a cellular and molecular point of view, the main studies about osteomimicry of mammary cells in vitro are attributable to the group of Maria Morgan [9–11]. Indeed, Morgan and colleagues for the first time demonstrated that 3D collagen glycosaminoglycan scaffolds, bioengineered to represent the bone microenvironment, are capable of supporting the growth and mineralization of mammary cell line (4T1)[10].